Details of the Researcher

PHOTO

Naoto Ishii
Section
Graduate School of Medicine
Job title
Professor
Degree

  • 博士（医学）（東北大学）

Education 2

  • Tohoku University　Graduate School, Division of Medicine

    - 1995/03/26

  • Tohoku University　Faculty of Medicine

    - 1989/03/26

Committee Memberships 7

  • 日本学術会議　連携会員

    2014/10 - Present

  • 日本免疫学会　評議員

    2009/10 - Present

  • 日本細菌学会東北支部会　評議員

    2003/04 - Present

  • 日本学術振興会・学術システム研究センター　専門研究員

    2018/04 - 2022/03

  • 秋田県　秋田県立高校学術顧問

    2014/06 - 2018/05

  • 日本免疫学会　理事

    2012/10 - 2016/12

  • 日本免疫学会　理事・財務委員長

    2012/10 - 2016/12

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Professional Memberships 7

  • American association of immnologists

  • THE JAPANESE SOCIETY OF PEDIATRIC HEMATOLOGY/ONCOLOGY

  • THE JAPANESE CANCER ASSOCIATION

  • JAPANESE SOCIETY OF ALLERGOLOGY

  • JAPAN PEDIATRIC SOCIETY

  • THE JAPANESE SOCIETY FOR IMMUNOLOGY

  • JAPANESE SOCIETY FOR BACTERIOLOGY

︎Show all ︎Show first 5

Research Interests 4

  • アレルギー

  • Immunodeficiency

  • Autoimmunity

  • T cell immunity

Research Areas 3

  • Life sciences / Experimental pathology /

  • Life sciences / Fetal medicine/Pediatrics / Pediatrics

  • Life sciences / Immunology / Immunology

Awards 2

  1. 平成１５年度宮城県医師会医学奨励賞

    2004/01　宮城県医師会

  2. 平成１５年度東北大学医学部奨学賞 金賞

    2004/01　東北大学医学部

Papers 165

  1. Supersulfide controls intestinal inflammation by suppressing CD4+ T cell proliferation

    Shunichi Tayama, Yuya Kitamura, Kyoga Hiraide, Hibiki Suzuki, Jing Li, Ziying Yang, Ryoji Mitsuwaka, Akihisa Kawajiri, Kosuke Sato, Feng Gao, Taku Nakai, Yuko Okuyama, Tadahisa Numakura, Mitsuhiro Yamada, Tomoaki Ida, Masanobu Morita, Takeshi Kawabe, Takaaki Akaike, Naoto Ishii

    Frontiers in Immunology　16　2025/04/15

    Publisher: Frontiers Media SA

    DOI： 10.3389/fimmu.2025.1506580 　

    eISSN： 1664-3224

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    Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation where CD4+ T lymphocytes play an essential role. Accumulating evidence suggests that immune responses driven by CD4+ T cells are critically regulated by various metabolic pathways including oxidative phosphorylation and glycolysis. Here we show that CARS2/CPERS-dependent supersulfide metabolism restrains CD4+ T cell proliferation in a cell-intrinsic manner. Under steady state, Cars2+/- mice exhibited spontaneous accumulation of effector/memory CD4+ T cells in the colon with age. In lymphopenic conditions, Cars2+/- CD4+ T cells showed enhanced cell cycle entry with reduced expression of a cell cycle inhibitor Trp53 and triggered an exacerbated form of colitis, the response being rescued by treatment with a supersulfide donor glutathione trisulfide (GSSSG). Furthermore, re-analysis of publicly available gene datasets of human colonic CD4+ T lymphocytes revealed that downregulation of CARS2 was associated with pathogenesis of IBD, and indeed, addition of GSSSG inhibited human CD4+ T cell proliferation in vitro. Together these observations reveal that CARS2/CPERS-dependent supersulfide metabolism is essential for homeostasis of intestinal effector/memory CD4+ T cells, and further suggest that dysregulation of the same metabolic pathway can lead to development of gut inflammation both in mice and humans.

  2. Naturally arising memory-phenotype CD4+ T lymphocytes give rise to multiple helper subsets to contribute to tumor immunity while inhibiting GVHD

    Ziying Yang, Jing Li, Hideaki Watanabe, Feng Gao, Akihisa Kawajiri, Keita Koinuma, Kosuke Sato, Yuko Okuyama, Shunichi Tayama, Yoichiro Iwakura, Naoto Ishii, Takeshi Kawabe

    Cancer Immunology Research　2025/04/01

    Publisher: American Association for Cancer Research (AACR)

    DOI： 10.1158/2326-6066.cir-24-0598 　

    ISSN： 2326-6066

    eISSN： 2326-6074

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    Abstract Memory-phenotype (MP) CD4+ T lymphocytes spontaneously develop in steady state from peripheral naïve precursors in a manner dependent on self-antigen recognition. While MP cells possess innate type 1 and 3 effector functions that can contribute to host defense and autoimmunity, their immunological functions in tumor immunity and graft-versus-host disease (GVHD), which results from therapeutic bone marrow transplantation (BMT) against hematological malignancies, remain unclear. Here we show that in mixed lymphocyte reactions, MP lymphocytes can generate T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cell subsets, whereas naïve cells dominantly differentiate to Th1. Consistent with this, naïve lymphocytes mainly induce Th1 responses in the mouse EL4 model of malignant lymphoma and the B16 model of malignant melanoma, whereas MP cells efficiently give rise to Th1, Th17, and Treg subsets to exert mild, IFN--dependent antitumor activities in vivo. Moreover, we demonstrate using a mouse model of BMT that MP cells more efficiently differentiate into Treg cells to partially suppress GVHD as compared to naïve T lymphocytes. Furthermore, our data suggest that when used as donor T lymphocytes in BMT in tumor-bearing mice, MP cells give rise to Th1, Th17, and Treg cells to generate antitumor responses without inducing GVHD. Together these results identify MP cells as a unique T-cell population that has potential to generate multiple T helper subsets including Th1 and Treg cells, thereby contributing to tumor immunity while inhibiting development of BMT-associated GVHD.

  3. Naturally arising memory-phenotype CD4 + T lymphocytes contain an undifferentiated population that can generate T H 1, T H 17, and T reg cells

    Akihisa Kawajiri, Jing Li, Keita Koinuma, Ziying Yang, Hye Jin Yoon, Jaeu Yi, Hiroyuki Nagashima, Minami Ishii, Feng Gao, Kosuke Sato, Shunichi Tayama, Hideo Harigae, Yoichiro Iwakura, Naoto Ishii, Alan Sher, Kazuyoshi Ishigaki, Jinfang Zhu, Kwang Soon Kim, Takeshi Kawabe

    Science Advances　10　(49)　2024/12/06

    Publisher: American Association for the Advancement of Science (AAAS)

    DOI： 10.1126/sciadv.adq6618 　

    eISSN： 2375-2548

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    Memory-phenotype (MP) CD4 + T lymphocytes develop from naïve cells via self-recognition at homeostasis. While previous studies defined MP cells as a heterogeneous population that comprises T helper 1 (T H 1)/17–like subsets, functional significance of the T-bet − Rorγt − subpopulation remains unknown. Here we show that MP lymphocytes as a whole population can differentiate into T H 1/17/regulatory T (T reg ) cells to mediate mild and persistent inflammation in lymphopenic environments, whereas naïve cells exhibit strong, T H 1-dominated responses. Moreover, we demonstrate that MP lymphocytes comprise not only T H 1/17-differentiated subsets but a polyclonal, transcriptomically immature “undifferentiated” subpopulation at homeostasis. Furthermore, our data argue that while the T-bet + Rorγt − MP subset is terminally T H 1-differentiated, its undifferentiated counterpart retains the capacity to rapidly proliferate to differentiate into T H 1/17/T reg cells, with the latter response tonically constrained by preexisting T reg cells. Together, our results identify undifferentiated MP CD4 + T lymphocytes as a unique precursor that has a diverse differentiation potential to generate T H 1/17/T reg cells to contribute to pathogenesis of inflammation.

  4. Excess generation and activation of naturally arising memory-phenotype CD4+ T lymphocytes are inhibited by regulatory T cells in steady state

    Jing Li, Ziying Yang, Akihisa Kawajiri, Kosuke Sato, Shunichi Tayama, Naoto Ishii, Jinfang Zhu, Takeshi Kawabe

    Frontiers in Immunology　15　2024/08/16

    Publisher: Frontiers Media SA

    DOI： 10.3389/fimmu.2024.1429954 　

    eISSN： 1664-3224

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    Conventional CD4+ T lymphocytes consist of naïve, foreign antigen-specific memory, and self-antigen-driven memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells tonically proliferate in response to self-antigens and differentiate into the T-bet+ subset in steady state. How excess proliferation and differentiation of MP cells are inhibited remains unclear. Given immunosuppressive function of regulatory T cells (Tregs), it is possible that they are also involved in inhibition of spontaneous MP cell activation. Here we show using Foxp3-diphtheria toxin receptor-transgenic mice that both MP and naïve CD4+ T cells spontaneously proliferate and differentiate into Th1 cells upon acute Treg depletion. At an early time point post Treg depletion, MP as compared to naïve CD4+ T cells are preferentially activated while at a later stage, the response is dominated by activated cells originated from the naïve pool. Moreover, we argue that MP cell proliferation is driven by TCR and CD28 signaling whereas Th1 differentiation mediated by IL-2. Furthermore, our data indicate that such activation of MP and naïve CD4+ T lymphocytes contribute to development of multi-organ inflammation at early and later time points, respectively, after Treg ablation. Together our findings reveal that Tregs tonically inhibit early, spontaneous proliferation and Th1 differentiation of MP CD4+ T lymphocytes as well as late activation of naïve cells, thereby contributing to maintenance of T cell homeostasis.

  5. Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes. International-journal

    Hodaka Nagai, Mitsuki Azuma, Ayaka Sato, Nagito Shibui, Sayaka Ogawara, Yuta Tsutsui, Ayano Suzuki, Tomomi Wakaizumi, Aya Ito, Shimpei Matsuyama, Masashi Morita, Mari Hikosaka Kuniishi, Naoto Ishii, Takanori So

    Cells　12　(12)　2023/06/09

    DOI： 10.3390/cells12121596 　

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    The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc-scOX40L, Fc-sc4-1BBL, Fc-scCD27L (CD70) and Fc-scGITRL. Without intentional cross-linking, these soluble Fc-scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc-scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc-scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins.

  6. CD3鎖を標的とした超硫黄分子によるTCRシグナルを介した免疫応答制御

    守田 匡伸, 山田 充啓, 佐々木 優作, 井田 智章, 松永 哲郎, 高田 剛, 渡部 聡, 稲葉 謙次, 石井 直人, 杉浦 久敏, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　95回　3P-132　2022/11

    Publisher: (公社)日本生化学会

  7. CD3鎖を標的とした超硫黄分子によるTCRシグナルを介した免疫応答制御

    守田 匡伸, 山田 充啓, 佐々木 優作, 井田 智章, 松永 哲郎, 高田 剛, 渡部 聡, 稲葉 謙次, 石井 直人, 杉浦 久敏, 本橋 ほづみ

    日本生化学会大会プログラム・講演要旨集　95回　3P-132　2022/11

    Publisher: (公社)日本生化学会

  8. Staphylococcus aureus skin colonization promotes SLE-like autoimmune inflammation via neutrophil activation and the IL-23/IL-17 axis. International-journal

    Hitoshi Terui, Kenshi Yamasaki, Moyuka Wada-Irimada, Mayuko Onodera-Amagai, Naokazu Hatchome, Masato Mizuashi, Riu Yamashita, Takeshi Kawabe, Naoto Ishii, Takaaki Abe, Yoshihide Asano, Setsuya Aiba

    Science immunology　7　(76)　eabm9811　2022/10/28

    DOI： 10.1126/sciimmunol.abm9811 　

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    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation of various organs such as skin, kidneys, bones, and brain and the presence of autoantibodies. Although the cause of SLE is not completely understood, environmental factors, genetic susceptibility, hormone factors, and environmental factors are thought to play essential roles in the pathogenesis of SLE. Among environmental factors, the microbiota are linked to the development of different autoimmune diseases. The microbiota in the nasal cavity and gut are involved in SLE development, but the influence of skin microbiota is still unclear. Here, we demonstrated that epithelial cell-specific IκBζ-deficient (NfkbizΔK5) mice showed spontaneous skin inflammation with increased abundance of Staphylococcus aureus on the skin. When S. aureus was epicutaneously applied on NfkbizΔK5 mice, NfkbizΔK5 mice developed SLE-associated autoantibodies, anti-dsDNA antibodies, anti-Sm antibodies, and glomerulonephritis with IgG deposition. Epicutaneous S. aureus application significantly increased staphylococcal colonization on the skin of NfkbizΔK5 mice with reduced expression of several antimicrobial peptides in the skin. This staphylococcal skin colonization promoted caspase-mediated keratinocyte apoptosis and neutrophil activation, inducing the interleukin-23 (IL-23)/IL-17 immune response by activating dendritic cells and T cells. Furthermore, the subcutaneous administration of anti-IL-23p19 and anti-IL-17A antibodies alleviated the systemic autoimmune response. Together, these findings underscore epithelial-immune cross-talk disturbances caused by skin dysbiosis as an essential mediator inducing autoimmune diseases.

  9. Functional Analysis of the Transcriptional Regulator IκB-ζ in Intestinal Homeostasis

    Tomoki Sasaki, Hiroyuki Nagashima, Atsushi Okuma, Takeshi Yamauchi, Kenshi Yamasaki, Setsuya Aiba, Takanori So, Naoto Ishii, Yuji Owada, Takashi MaruYama, Shuhei Kobayashi

    Digestive Diseases and Sciences　67　(4)　1252-1259　2022/04/05

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s10620-021-06958-8 　

    ISSN： 0163-2116

    eISSN： 1573-2568

  10. 幅広い臨床症状を呈したMECOM遺伝子変異を同定した2家系

    新堀 哲也, 田野島 玲大, 笹原 洋二, 佐藤 篤, 入江 正寛, 南條 由佳, 舟山 亮, 城田 松之, 阿部 太紀, 奥山 祐子, 石井 直人, 中山 啓子, 呉 繁夫, 今泉 益栄, 青木 洋子

    日本小児科学会雑誌　126　(2)　230-230　2022/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  11. TNF Receptor-Associated Factor 5 Limits IL-27 Receptor Signaling in CD4+ T Lymphocytes. International-journal

    Eigo Kawahara, Mitsuki Azuma, Hiroyuki Nagashima, Koki Omori, Sho Akiyama, Yuka Fujimori, Mayu Oishi, Nagito Shibui, Kosuke Kawaguchi, Masashi Morita, Yuko Okuyama, Naoto Ishii, Takanori So

    Journal of immunology (Baltimore, Md. : 1950)　208　(3)　642-650　2022/02/01

    DOI： 10.4049/jimmunol.2001358 　

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    TNF receptor-associated factor 5 (TRAF5) restrains early signaling activity of the IL-6 receptor in naive CD4+ T cells by interacting with the shared gp130 chain, although TRAF5 was initially discovered as a cytoplasmic adaptor protein to activate signaling mediated by TNF receptor family molecules. This leads to the question of whether TRAF5 limits signaling via the receptor for IL-27, which is composed of gp130 and WSX-1. The aim of this study is to clarify the role of TRAF5 in IL-27 receptor signaling and to understand the differential role of TRAF5 on cytokine receptor signaling. We found that Traf5 -/- CD4+ T cells displayed significantly higher levels of phosphorylated STAT1 and STAT-regulated genes Socs3 and Tbx21, as early as 1 h after IL-27 exposure when compared with Traf5 +/+ CD4+ T cells. Upon IL-27 and TCR signals, the Traf5 deficiency significantly increased the induction of IL-10 and promoted the proliferation of CD4+ T cells. Traf5 -/- mice injected with IL-27 displayed significantly enhanced delayed-type hypersensitivity responses, demonstrating that TRAF5 works as a negative regulator for IL-27 receptor signaling. In contrast, IL-2 and proliferation mediated by glucocorticoid-induced TNF receptor-related protein (GITR) and TCR signals were significantly decreased in Traf5 -/- CD4+ T cells, confirming that TRAF5 works as a positive regulator for cosignaling via GITR. Collectively, our results demonstrate that TRAF5 reciprocally controls signals mediated by the IL-27 receptor and GITR in CD4+ T cells and suggest that the regulatory activity of TRAF5 in gp130 is distinct from that in TNF receptor family molecules in a T cell.

  12. Phenotypic heterogeneity in individuals with MECOM variants in 2 families. International-journal

    Tetsuya Niihori, Reo Tanoshima, Yoji Sasahara, Atsushi Sato, Masahiro Irie, Yuka Saito-Nanjo, Ryo Funayama, Matsuyuki Shirota, Taiki Abe, Yuko Okuyama, Naoto Ishii, Keiko Nakayama, Shigeo Kure, Masue Imaizumi, Yoko Aoki

    Blood advances　6　(18)　5257-5261　2022/01/12

    DOI： 10.1182/bloodadvances.2020003812 　

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    MECOM encodes the transcriptional regulators, EVI1 and MDS1-EVI1, from two distinct transcription start sites. EVI1 plays important roles in hematopoiesis and stem cell self-renewal. Recently, our group and others revealed that individuals with MECOM variants present diverse hematological and skeletal defects, including radioulnar synostosis (RUS). In the present study, we analyzed two families suspected with MECOM-associated syndrome. In family 1, a MECOM splicing variant (c.2285+1G>A) was identified in an individual with bone marrow failure (TRS4) without RUS and her mother, who had mild leukocytopenia, thrombocytopenia, and bilateral RUS. A copy neutral loss of heterozygosity decreasing the variant allele frequency was observed in the bone marrow of TRS4 and the peripheral blood leukocytes of her mother. However, TRS4 remained transfusion-dependent. In family 2, a MECOM variant (c.2208-4A>G), which was predicted to cause a cryptic acceptor site that results in a 3-base insertion (an insertion of Ser) in the mRNA, was identified in the proband, with bone marrow failure; this variant was also observed in her brother and father, both of whom have skeletal malformations, but no cytopenia. RT-PCR using leukocytes revealed a transcript with a 3-bp insertion in the proband, her brother, and the father, suggesting that the transcript variant with a 3-bp insertion is independent of blood phenotype. Collectively, these results suggest the presence of intrafamilial clinical heterogeneity in both families with MECOM splicing variants. Somatic genetic event may complicate the understanding of clinical variability among family members.

  13. OX40 Ligand-Mannose-Binding Lectin Fusion Protein Induces Potent OX40 Cosignaling in CD4+ T Cells.

    Ayaka Sato, Mitsuki Azuma, Hodaka Nagai, Wakana Imai, Kosuke Kawaguchi, Masashi Morita, Yuko Okuyama, Naoto Ishii, Takanori So

    Biological & pharmaceutical bulletin　45　(12)　1798-1804　2022

    DOI： 10.1248/bpb.b22-00493 　

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    OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is induced on activated T cells. Membrane-bound OX40 ligand (OX40L) expressed by activated antigen-presenting cells induces OX40 signaling, which promotes T cell immunity. OX40 agonism would be a potential target for immunotherapy, however, it remains unclear how the activity of OX40 can be successfully controlled by a designer OX40L protein. We prepared a soluble OX40L protein possessing a PA-peptide tag and a collagenous trimerization domain from mannose-binding lectin (MBL), and tested whether PA-MBL-OX40L fusion protein worked as an agonist for OX40. We found that the majority of recombinant PA-MBL-OX40L protein purified from culture supernatants displayed a trimer structure and bound to cell surface OX40 or OX40-Fc fusion protein in a dose-dependent manner. Upon stimulation of CD4+ T cells with TCR/CD3 without CD28, PA-MBL-OX40L displayed significantly increased proliferative and cytokine responses when compared with a benchmark agonistic monoclonal antibody for OX40. Both soluble and immobilized forms of PA-MBL-OX40L induced potent OX40 signaling in CD4+ T cells. Mice administered with PA-MBL-OX40L displayed significantly augmented T cell-mediated delayed-type hypersensitivity responses. Our results suggest that activity of OX40L could be engineered to elicit better T cell responses by rational design of its assembly and architecture.

  14. Redefining the Foreign Antigen and Self-Driven Memory CD4+ T-Cell Compartments via Transcriptomic, Phenotypic, and Functional Analyses. International-journal

    Takeshi Kawabe, Thomas Ciucci, Kwang Soon Kim, Shunichi Tayama, Akihisa Kawajiri, Takumi Suzuki, Riou Tanaka, Naoto Ishii, Dragana Jankovic, Jinfang Zhu, Jonathan Sprent, Rémy Bosselut, Alan Sher

    Frontiers in immunology　13　870542-870542　2022

    DOI： 10.3389/fimmu.2022.870542 　

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    Under steady-state conditions, conventional CD4+ T lymphocytes are classically divided into naïve (CD44lo CD62Lhi) and memory (CD44hi CD62Llo) cell compartments. While the latter population is presumed to comprise a mixture of distinct subpopulations of explicit foreign antigen (Ag)-specific "authentic" memory and foreign Ag-independent memory-phenotype (MP) cells, phenotypic markers differentially expressed in these two cell types have yet to be identified. Moreover, while MP cells themselves have been previously described as heterogeneous, it is unknown whether they consist of distinct subsets defined by marker expression. In this study, we demonstrate using combined single-cell RNA sequencing and flow cytometric approaches that self-driven MP CD4+ T lymphocytes are divided into CD127hi Sca1lo, CD127hi Sca1hi, CD127lo Sca1hi, and CD127lo Sca1lo subpopulations that are Bcl2lo, while foreign Ag-specific memory cells are CD127hi Sca1hi Bcl2hi. We further show that among the four MP subsets, CD127hi Sca1hi lymphocytes represent the most mature and cell division-experienced subpopulation derived from peripheral naïve precursors. Finally, we provide evidence arguing that this MP subpopulation exerts the highest responsiveness to Th1-differentiating cytokines and can induce colitis. Together, our findings define MP CD4+ T lymphocytes as a unique, self-driven population consisting of distinct subsets that differ from conventional foreign Ag-specific memory cells in marker expression and establish functional relevance for the mature subset of CD127hi Sca1hi MP cells.

  15. コロナ禍における医学生のストレスとその解決方法に関する一考察

    岩崎 淳也, 加賀谷 豊, 石井 誠一, 齋木 由利子, 田中 淳一, 石井 直人

    医学教育　52　(Suppl.)　164-164　2021/07

    Publisher: (一社)日本医学教育学会

    ISSN： 0386-9644

  16. Fatty acid-binding protein 3 controls contact hypersensitivity through regulating skin dermal Vγ4+ γ/δ T cell in a murine model. International-journal

    Shuhei Kobayashi, Hai The Phung, Yoshiteru Kagawa, Hirofumi Miyazaki, Yu Takahashi, Atsuko Asao, Takashi Maruyama, Akihiko Yoshimura, Naoto Ishii, Yuji Owada

    Allergy　76　(6)　1776-1788　2021/06

    DOI： 10.1111/all.14630 　

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    BACKGROUND: Fatty acid-binding protein 3 (FABP3) is a cytosolic carrier protein of polyunsaturated fatty acids (PUFAs) and regulates cellular metabolism. However, the physiological functions of FABP3 in immune cells and how FABP3 regulates inflammatory responses remain unclear. METHODS: Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin wild-type and Fabp3-/- mice. Skin inflammation was assessed using FACS, histological, and qPCR analyses. The development of γ/δ T cells was evaluated by a co-culture system with OP9/Dll1 cells in the presence or absence of transgene of FABP3. RESULTS: Fabp3-deficient mice exhibit a more severe phenotype of contact hypersensitivity (CHS) accompanied by infiltration of IL-17-producing Vγ4+ γ/δ T cells that critically control skin inflammation. In Fabp3-/- mice, we found a larger proportion of Vγ4+ γ/δ T cells in the skin, even though the percentage of total γ/δ T cells did not change at steady state. Similarly, juvenile Fabp3-/- mice also contained a higher amount of Vγ4+ γ/δ T cells not only in the skin but in the thymus when compared with wild-type mice. Furthermore, thymic double-negative (DN) cells expressed FABP3, and FABP3 negatively regulates the development of Vγ4+ γ/δ T cells in the thymus. CONCLUSIONS: These findings suggest that FABP3 functions as a negative regulator of skin inflammation through limiting pathogenic Vγ4+ γ/δ T-cell generation in the thymus.

  17. Dysregulation of Rnf 213 gene contributes to T cell response via antigen uptake, processing, and presentation. International-journal

    Ryosuke Tashiro, Kuniyasu Niizuma, Jun Kasamatsu, Yuko Okuyama, Sherif Rashad, Atsuo Kikuchi, Miki Fujimura, Shigeo Kure, Naoto Ishii, Teiji Tominaga

    Journal of cellular physiology　236　(11)　7554-7564　2021/05/10

    DOI： 10.1002/jcp.30396 　

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    Growing evidence suggest the association between Moyamoya disease (MMD) and immune systems, such as antigen presenting cells in particular. Rnf213 gene, a susceptibility gene for MMD, is highly expressed in immune tissues, however, its function remains unclear. In addition, the physiological role of RNF213 gene polymorphism c.14576G > A (rs112735431), susceptibility variant for MMD, is also poorly understood. By studying Rnf213-knockout (Rnf213-KO) mice with deletion of largest exon32 and Rnf213-knockin (Rnf213-KI) mice with insertion of single-nucleotide polymorphism corresponding to c.14576G > A mutation in MMD patients, we aimed to investigate the role of RNF213 in dendritic cell development, and antigen processing and presentation. First, we found a high level of Rnf213 gene expression in conventional DCs and monocytes. Second, flow cytometric and confocal microscopic analysis revealed ovalbumin protein-pulsed Rnf213-KO and Rnf213-KI DCs showed impaired antigen uptake, proteolysis and reduced numbers of endosomes and lysosomes, and thereby failed to activate and proliferate antigen-specific T cells efficiently. In addition, Rnf213-KI DCs showed a similar phenotype to that of Rnf213-KO BMDCs. In conclusion, our findings suggest the critical role of RNF213 in antigen uptake, processing and presentation.

  18. Costello症候群モデルマウスにおけるアレルゲンによる皮膚炎の誘発と病態メカニズムの解明

    堅田 有宇, 井上 晋一, 浅尾 敦子, 小林 周平, 照井 仁, 井上 彩, 阿部 太紀, 新堀 哲也, 相場 節也, 石井 直人, 呉 繁夫, 青木 洋子

    日本小児科学会雑誌　125　(2)　292-292　2021/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  19. The Curcumin Analog GO-Y030 Controls the Generation and Stability of Regulatory T Cells. International-journal

    Takashi MaruYama, Shuhei Kobayashi, Hiroko Nakatsukasa, Yuki Moritoki, Daiki Taguchi, Yoichi Sunagawa, Tatsuya Morimoto, Atsuko Asao, Wenwen Jin, Yuji Owada, Naoto Ishii, Yoshiharu Iwabuchi, Akihiko Yoshimura, WanJun Chen, Hiroyuki Shibata

    Frontiers in immunology　12　687669-687669　2021

    DOI： 10.3389/fimmu.2021.687669 　

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    Regulatory T cells (Tregs) play a crucial role in preventing antitumor immune responses in cancer tissues. Cancer tissues produce large amounts of transforming growth factor beta (TGF-β), which promotes the generation of Foxp3+ Tregs from naïve CD4+ T cells in the local tumor microenvironment. TGF-β activates nuclear factor kappa B (NF-κB)/p300 and SMAD signaling, which increases the number of acetylated histones at the Foxp3 locus and induces Foxp3 gene expression. TGF-β also helps stabilize Foxp3 expression. The curcumin analog and antitumor agent, GO-Y030, prevented the TGF-β-induced generation of Tregs by preventing p300 from accelerating NF-κB-induced Foxp3 expression. Moreover, the addition of GO-Y030 resulted in a significant reduction in the number of acetylated histones at the Foxp3 promoter and at the conserved noncoding sequence 1 regions that are generated in response to TGF-β. In vivo tumor models demonstrated that GO-Y030-treatment prevented tumor growth and reduced the Foxp3+ Tregs population in tumor-infiltrating lymphocytes. Therefore, GO-Y030 exerts a potent anticancer effect by controlling Treg generation and stability.

  20. Requirements for the differentiation of innate T-bethigh memory-phenotype CD4+ T lymphocytes under steady state

    Takeshi Kawabe, Jaeu Yi, Akihisa Kawajiri, Kerry Hilligan, Difeng Fang, Naoto Ishii, Hidehiro Yamane, Jinfang Zhu, Dragana Jankovic, Kwang Soon Kim, Giorgio Trinchieri, Alan Sher

    Nature Communications　11　(1)　2020/12/01

    Publisher: Nature Research

    DOI： 10.1038/s41467-020-17136-1 　

    ISSN： 2041-1723

  21. GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity. International-journal

    Tsuyoshi Sakurai, Yuko Okuyama, Shuhei Kobayashi, Hai The Phung, Atsuko Asao, Takeshi Kawabe, Lishomwa C Ndhlovu, Carlo Riccardi, Hironori Kudo, Motoshi Wada, Masaki Nio, Takanori So, Naoto Ishii

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　34　(11)　14820-14831　2020/11

    DOI： 10.1096/fj.202001675R 　

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    Glucocorticoid-induced TNFR family related gene (GITR) is a member of the TNFR superfamily that is expressed on cells of the immune system. Although the protective and pathogenic roles of GITR in T cell immunity are well characterized, the role of GITR in innate immunity in the intestinal tissues has not been well clarified. In this study, using a dextran sulfate sodium (DSS)-induced colitis model in mice, we found that GITR-deficiency rendered mice more susceptible to acute intestinal inflammation and that a significantly higher number of activated natural killer (NK) cells was accumulated in the colonic lamina propria of Gitr-/- mice as compared to wild-type mice. Additionally, Rag2-/- Gitr-/- mice, which lack T cells but have NK cells, also displayed more severe colonic inflammation than Rag2-/- mice. In contrast, an anti-GITR agonistic antibody significantly alleviated colitis in Rag2-/- mice. Engagement of GITR inhibited IL-15-mediated activating signaling events in NK cells, which include cell activation and proliferation, and production of cytokines and cytotoxic granules. Taken together, our results provide the first evidence that GITR negatively controls intestinal inflammation through NK cell functions.

  22. Fatty acid-binding protein 5 limits ILC2-mediated allergic lung inflammation in a murine asthma model. International-journal

    Shuhei Kobayashi, Shunichi Tayama, Hai The Phung, Yoshiteru Kagawa, Hirofumi Miyazaki, Yu Takahashi, Takashi Maruyama, Naoto Ishii, Yuji Owada

    Scientific reports　10　(1)　16617-16617　2020/10/06

    DOI： 10.1038/s41598-020-73935-y 　

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    Dietary obesity is regarded as a problem worldwide, and it has been revealed the strong linkage between obesity and allergic inflammation. Fatty acid-binding protein 5 (FABP5) is expressed in lung cells, such as alveolar epithelial cells (ECs) and alveolar macrophages, and plays an important role in infectious lung inflammation. However, we do not know precise mechanisms on how lipid metabolic change in the lung affects allergic lung inflammation. In this study, we showed that Fabp5-/- mice exhibited a severe symptom of allergic lung inflammation. We sought to examine the role of FABP5 in the allergic lung inflammation and demonstrated that the expression of FABP5 acts as a novel positive regulator of ST2 expression in alveolar ECs to generate retinoic acid (RA) and supports the synthesis of RA from type II alveolar ECs to suppress excessive activation of innate lymphoid cell (ILC) 2 during allergic lung inflammation. Furthermore, high-fat diet (HFD)-fed mice exhibit the downregulation of FABP5 and ST2 expression in the lung tissue compared with normal diet (ND)-fed mice. These phenomena might be the reason why obese people are more susceptible to allergic lung inflammation. Thus, FABP5 is potentially a therapeutic target for treating ILC2-mediated allergic lung inflammation.

  23. Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage. International-journal

    Eikan Mishima, Mariko Ichijo, Takeshi Kawabe, Koichi Kikuchi, Yukako Akiyama, Takafumi Toyohara, Takehiro Suzuki, Chitose Suzuki, Atsuko Asao, Naoto Ishii, Shinji Fukuda, Takaaki Abe

    Toxins　12　(9)　2020/08/26

    DOI： 10.3390/toxins12090547 　

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    Alterations in microbiota are known to affect kidney disease conditions. We have previously shown that germ-free conditions exacerbated adenine-induced kidney damage in mice; however, the mechanism by which this occurs has not been elucidated. To explore this mechanism, we examined the influence of germ-free conditions on purine metabolism and renal immune responses involved in the kidney damage. Germ-free mice showed higher expression levels of purine-metabolizing enzymes such as xanthine dehydrogenase, which converts adenine to a nephrotoxic byproduct 2,8-dihydroxyadenine (2,8-DHA). The germ-free mice also showed increased urinary excretion of allantoin, indicating enhanced purine metabolism. Metabolome analysis demonstrated marked differences in the purine metabolite levels in the feces of germ-free mice and mice with microbiota. Furthermore, unlike the germ-free condition, antibiotic treatment did not increase the expression of purine-metabolizing enzymes or exacerbate adenine-induced kidney damage. Considering renal immune responses, the germ-free mice displayed an absence of renal IL-17A expression. However, the adenine-induced kidney damage in wild-type mice was comparable to that in IL-17A-deficient mice, suggesting that IL-17A does not play a major role in the disease condition. Our results suggest that the enhanced host purine metabolism in the germ-free mice potentially promotes the conversion of the administered adenine into 2,8-DHA, resulting in exacerbated kidney damage. This further suggests a role of the microbiota in regulating host purine metabolism.

  24. Costello syndrome model mice with a HrasG12S/+ mutation are susceptible to develop house dust mite-induced atopic dermatitis. International-journal

    Yu Katata, Shin-Ichi Inoue, Atsuko Asao, Shuhei Kobayashi, Hitoshi Terui, Aya Inoue-Shibui, Taiki Abe, Tetsuya Niihori, Setsuya Aiba, Naoto Ishii, Shigeo Kure, Yoko Aoki

    Cell death & disease　11　(8)　617-617　2020/08/13

    DOI： 10.1038/s41419-020-02845-8 　

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    Costello syndrome is an autosomal dominant disorder that is caused by germline HRAS mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an Hras G12S mutation (HrasG12S/+ mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (Dermatophagoides farinae, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of HrasG12S/+ mice compared with Hras+/+ mice. Cultured HrasG12S/+ keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in HrasG12S/+ mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of HrasG12S/+ mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of HrasG12S/+ mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.

  25. Fatty acid-binding protein 3 regulates differentiation of IgM-producing plasma cells Peer-reviewed

    Kobayashi S, Phung HT, Tayama S, Kagawa Y, Miyazaki H, Yamamoto Y, Maruyama T, Ishii N, Owada Y

    2020/06

  26. Correction: TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells. International-journal

    Hai The Phung, Hiroyuki Nagashima, Shuhei Kobayashi, Naoki Asano, Tomoaki Machiyama, Tsuyoshi Sakurai, Shunichi Tayama, Atsuko Asao, Akira Imatani, Takeshi Kawabe, Yuko Okuyama, Naoto Ishii, Takanori So

    ImmunoHorizons　4　(4)　216-216　2020/04/23

    DOI： 10.4049/immunohorizons.2000022 　

  27. Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome Peer-reviewed

    Sou Niitsuma, Hiroki Kudo, Atsuo Kikuchi, Takaya Hayashi, Satoshi Kumakura, Shuhei Kobayashi, Yuko Okuyama, Naonori Kumagai, Tetsuya Niihori, Yoko Aoki, Takanori So, Ryo Funayama, Keiko Nakayama, Matsuyuki Shirota, Shuji Kondo, Shoji Kagami, Hiroyasu Tsukaguchi, Kazumoto Iijima, Shigeo Kure, Naoto Ishii

    International immunology　32　(4)　283-292　2020/04

    DOI： 10.1093/intimm/dxz081 　

    eISSN： 1460-2377

  28. TRAF5 Deficiency Ameliorates the Severity of Dextran Sulfate Sodium Colitis by Decreasing TRAF2 Expression in Nonhematopoietic Cells. International-journal Peer-reviewed

    Hai The Phung, Hiroyuki Nagashima, Shuhei Kobayashi, Naoki Asano, Tomoaki Machiyama, Tsuyoshi Sakurai, Shun-Ichi Tayama, Atsuko Asao, Akira Imatani, Takeshi Kawabe, Yuko Okuyama, Naoto Ishii, Takanori So

    ImmunoHorizons　4　(3)　129-139　2020/03/10

    DOI： 10.4049/immunohorizons.2000007 　

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    TNFR-associated factor 5 (TRAF5) is a cytosolic adaptor protein and functions as an inflammatory regulator. However, the in vivo function of TRAF5 remains unclear, and how TRAF5 controls inflammatory responses in the intestine is not well understood. In this study, we found that intestinal epithelial cells from Traf5-/- mice expressed a significantly lower level of NF-κB-regulated proinflammatory genes, such as Tnf, Il6, and Cxcl1, as early as day 3 after dextran sulfate sodium (DSS) exposure when compared with wild-type mice. The intestinal barrier integrity of DSS-treated Traf5-/- mice remained intact at this early time point, and Traf5-/- mice showed decreased body weight loss and longer colon length at later time points. Surprisingly, the protein level of TRAF2, but not TRAF3, was reduced in colon tissues of Traf5-/- mice after DSS, indicating the requirement of TRAF5 for TRAF2 protein stability in the inflamed colon. Experiments with bone marrow chimeras confirmed that TRAF5 deficiency in nonhematopoietic cells caused the attenuated colitis. Our in vitro experiments demonstrated that proinflammatory cytokines significantly promoted the degradation of TRAF2 protein in Traf5-/- nonhematopoietic cells in a proteasome-dependent manner. Collectively, our data suggest a novel regulatory function of TRAF5 in supporting the proinflammatory function of TRAF2 in nonhematopoietic cells, which may be important for acute inflammatory responses in the intestine.

  29. Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. International-journal Peer-reviewed

    Shinichi Kuriyama, Hirohito Metoki, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Masato Nagai, Hiroko Matsubara, Tomoko Kobayashi, Junichi Sugawara, Gen Tamiya, Atsushi Hozawa, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Akira Narita, Mana Kogure, Takumi Hirata, Ichiro Tsuji, Fuji Nagami, Nobuo Fuse, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Yoichi Suzuki, Noriko Osumi, Keiko Nakayama, Kiyoshi Ito, Shinichi Egawa, Koichi Chida, Eiichi Kodama, Hideyasu Kiyomoto, Tadashi Ishii, Akito Tsuboi, Hiroaki Tomita, Yasuyuki Taki, Hiroshi Kawame, Kichiya Suzuki, Naoto Ishii, Soichi Ogishima, Satoshi Mizuno, Takako Takai-Igarashi, Naoko Minegishi, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Osamu Tanabe, Seizo Koshiba, Hiroaki Hashizume, Hozumi Motohashi, Teiji Tominaga, Sadayoshi Ito, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Jiro Hitomi, Makoto Sasaki, Kengo Kinoshita, Hiroshi Tanaka, Tadao Kobayashi, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

    International journal of epidemiology　49　(1)　18-19　2020/02/01

    DOI： 10.1093/ije/dyz169 　

    ISSN： 0300-5771

  30. Study profile of The Tohoku Medical Megabank Community-Based Cohort Study. Peer-reviewed

    Atsushi Hozawa, Kozo Tanno, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Akira Narita, Mana Kogure, Kotaro Nochioka, Ryohei Sasaki, Nobuyuki Takanashi, Kotaro Otsuka, Kiyomi Sakata, Shinichi Kuriyama, Masahiro Kikuya, Osamu Tanabe, Junichi Sugawara, Kichiya Suzuki, Yoichi Suzuki, Eiichi N Kodama, Nobuo Fuse, Hideyasu Kiyomoto, Hiroaki Tomita, Akira Uruno, Yohei Hamanaka, Hirohito Metoki, Mami Ishikuro, Taku Obara, Tomoko Kobayashi, Kazuyuki Kitatani, Takako Takai-Igarashi, Soichi Ogishima, Mamoru Satoh, Hideki Ohmomo, Akito Tsuboi, Shinichi Egawa, Tadashi Ishii, Kiyoshi Ito, Sadayoshi Ito, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Masao Nagasaki, Kazuhiko Igarashi, Seizo Koshiba, Ritsuko Shimizu, Gen Tamiya, Keiko Nakayama, Hozumi Motohashi, Jun Yasuda, Atsushi Shimizu, Tsuyoshi Hachiya, Yuh Shiwa, Teiji Tominaga, Hiroshi Tanaka, Kotaro Oyama, Ryoichi Tanaka, Hiroshi Kawame, Akimune Fukushima, Yasushi Ishigaki, Tomoharu Tokutomi, Noriko Osumi, Tadao Kobayashi, Fuji Nagami, Hiroaki Hashizume, Tomohiro Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Ryujin Endo, Satoshi Nishizuka, Ichiro Tsuji, Jiro Hitomi, Motoyuki Nakamura, Kuniaki Ogasawara, Nobuo Yaegashi, Kengo Kinoshita, Shigeo Kure, Akio Sakai, Seiichiro Kobayashi, Kenji Sobue, Makoto Sasaki, Masayuki Yamamoto

    Journal of epidemiology　31　(1)　65-76　2020/01/11

    DOI： 10.2188/jea.JE20190271 　

    ISSN： 0917-5040

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    BackgroundWe established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environmental interactions on the incidence of major diseases such as cancer and cardiovascular diseases.MethodsWe asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria was aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), for example, carotid echography, calcaneal ultrasound bone mineral density, and so on. All participants agreed to measure genome information and to distribute their information widely.ResultsAs a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants with Type 1 survey were more likely to have psychological distress than those of Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents regardless of sex.ConclusionThis cohort comprised large sample size and it contains information on disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

  31. IQ motif-containing GTPase-activating protein 1 is essential for the optimal maintenance of lung ILC2s. International-journal Peer-reviewed

    Tayama S, Okuyama Y, Phung HT, Asao A, Kobayashi S, Musha T, Machiyama T, Sakurai T, Zhang C, Ushio-Fukai M, Kawabe T, So T, Ishii N

    International immunology　32　(4)　233-241　2019/12

    DOI： 10.1093/intimm/dxz077 　

    ISSN： 0953-8178

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    Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 immunity and are crucial for pathogenesis of various types of inflammatory disease. IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein that is involved in multiple cellular functions such as cell survival and trafficking. While the roles for IQGAP1 in T and B lymphocytes have been uncovered, the physiological significance of IQGAP1 in innate lymphocytes remains to be elucidated. In the current study, we demonstrate that using bone marrow chimeras, the deficiency of IQGAP1 caused an impaired survival of lung ILC2s in a cell-intrinsic manner and that Iqgap1-/- mice displayed decreased accumulation of ILC2s after administration of papain and thereby reduced the pathology of the disease. Moreover, Iqgap1-/- ILC2s showed a significantly enhanced apoptosis as compared to wild-type ILC2s under both steady-state and inflammatory conditions. Together these results identify for the first time that IQGAP1 is essential for homeostasis of ILC2s in the lung.

  32. CD45+CD326+ Cells are Predictive of Poor Prognosis in Non-Small Cell Lung Cancer Patients. International-journal Peer-reviewed

    Kota Ishizawa, Mie Yamanaka, Yuriko Saiki, Eisaku Miyauchi, Shinichi Fukushige, Tetsuya Akaishi, Atsuko Asao, Takahiro Mimori, Ryota Saito, Yutaka Tojo, Riu Yamashita, Michiaki Abe, Akira Sakurada, Nhu-An Pham, Ming Li, Yoshinori Okada, Tadashi Ishii, Naoto Ishii, Seiichi Kobayashi, Masao Nagasaki, Masakazu Ichinose, Ming-Sound Tsao, Akira Horii

    Clinical cancer research : an official journal of the American Association for Cancer Research　25　(22)　6756-6763　2019/11/15

    DOI： 10.1158/1078-0432.CCR-19-0545 　

    ISSN： 1078-0432

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    PURPOSE: The epithelial-to-mesenchymal transition, the major process by which some cancer cells convert from an epithelial phenotype to a mesenchymal one, has been suggested to drive chemo-resistance and/or metastasis in patients with cancer. However, only a few studies have demonstrated the presence of CD45/CD326 doubly-positive cells (CD45/CD326 DPC) in cancer. We deployed a combination of cell surface markers to elucidate the phenotypic heterogeneity in non-small cell lung cancer (NSCLC) cells and identified a new subpopulation that is doubly-positive for epithelial and non-epithelial cell-surface markers in both NSCLC cells and patients' malignant pleural effusions. EXPERIMENTAL DESIGN: We procured a total of 39 patients' samples, solid fresh lung cancer tissues from 21 patients and malignant pleural effusion samples from 18 others, and used FACS and fluorescence microscopy to check their surface markers. We also examined the EGFR mutations in patients with known acquired EGFR mutations. RESULTS: Our data revealed that 0.4% to 17.9% of the solid tumor tissue cells and a higher percentage of malignant pleural effusion cells harbored CD45/CD326 DPC expressing both epithelial and nonepithelial surface markers. We selected 3 EGFR mutation patients and genetically confirmed that the newly identified cell population really originated from cancer cells. We also found that higher proportions of CD45/CD326 DPC are significantly associated with poor prognosis. CONCLUSIONS: In conclusion, varying percentages of CD45/CD326 DPC exist in both solid cancer tissue and malignant pleural effusion in patients with NSCLC. This CD45/CD326 doubly-positive subpopulation can be an important key to clinical management of patients with NSCLC.

  33. TNF Receptor-Associated Factor 5 Limits Function of Plasmacytoid Dendritic Cells by Controlling IFN Regulatory Factor 5 Expression. International-journal Peer-reviewed

    Kobayashi S, Sakurai T, So T, Shiota Y, Asao A, Phung HT, Tanaka R, Kawabe T, Maruyama T, Kanno E, Kawakami K, Owada Y, Ishii N

    Journal of immunology (Baltimore, Md. : 1950)　203　(6)　1447-1456　2019/09

    DOI： 10.4049/jimmunol.1900188 　

    ISSN： 0022-1767

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    The physiological functions of TNF receptor-associated factor 5 (TRAF5) in the skin inflammation and wound healing process are not well characterized. We found that Traf5-/- mice exhibited an accelerated skin wound healing as compared with wild-type counterparts. The augmented wound closure in Traf5-/- mice was associated with a massive accumulation of plasmacytoid dendritic cells (pDCs) into skin wounds and an enhanced expression of genes related to wound repair at skin sites. In accordance with this result, adoptive transfer of Traf5-/- pDCs, but not wild-type pDCs, into the injured skin area in wild-type recipient mice significantly promoted skin wound healing. The expression of skin-tropic chemokine receptor CXCR3 was significantly upregulated in Traf5-/- pDCs, and treatment with a CXCR3 inhibitor cancelled the promoted wound healing in Traf5-/- mice, suggesting a pivotal role of CXCR3 in pDC-dependent wound healing. Traf5-/- pDCs displayed significantly higher expression of IFN regulatory factor 5 (IRF5), which correlated with greater induction of proinflammatory cytokine genes and CXCR3 protein after stimulation with TLR ligands. Consistently, transduction of exogeneous TRAF5 in Traf5-/- pDCs normalized the levels of abnormally elevated proinflammatory molecules, including IRF5 and CXCR3. Furthermore, knockdown of IRF5 also rescued the abnormal phenotypes of Traf5-/- pDCs. Therefore, the higher expression and induction of IRF5 in Traf5-/- pDCs causes proinflammatory and skin-tropic characteristics of the pDCs, which may accelerate skin wound healing responses. Collectively, our results uncover a novel role of TRAF5 in skin wound healing that is mediated by IRF5-dependent function of pDCs.

  34. The role of fatty acid binding protein 7 in spinal cord astrocytes in a mouse model of experimental autoimmune encephalomyelitis. International-journal Peer-reviewed

    Kenyu Kamizato, Sho Sato, Subrata Kumar Shil, Banlanjo A Umaru, Yoshiteru Kagawa, Yui Yamamoto, Masaki Ogata, Yuki Yasumoto, Yuko Okuyama, Naoto Ishii, Yuji Owada, Hirofumi Miyazaki

    Neuroscience　409　120-129　2019/06/15

    DOI： 10.1016/j.neuroscience.2019.03.050 　

    ISSN： 0306-4522

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    Fatty acid binding protein 7 (FABP7) is expressed in astrocytes of the developing and mature central nervous system, and modulates astrocyte function by controlling intracellular fatty acid homeostasis. Astrocytes in the spinal cord have an important role in the process of myelin degeneration and regeneration. In the present study, the authors examined the role of FABP7 in astrocytes in a mouse model of experimental autoimmune encephalomyelitis (EAE), which is an established model of multiple sclerosis (MS). FABP7 was expressed in the white matter astrocytes and increased after EAE onset; particularly strong expression was observed in demyelinating regions. In FABP7-knockout (KO) mice, the onset of EAE symptoms occurred earlier than in wild type (WT) mice, and mRNA expression levels of inflammatory cytokines (IL-17 and TNF-α) were higher in FABP7-KO lumbar spinal cord than in WT lumbar spinal cord at early stage of EAE. Interestingly, however, the clinical score was significantly reduced in FABP7-KO mice compared with WT mice in the late phase of EAE. Moreover, the area exhibiting expression of fibronectin, which is an extracellular matrix protein mainly produced by astrocytes and inhibits remyelination of oligodendrocytes, was significantly decreased in FABP7-KO compared with WT mice. Collectively, FABP7 in astrocyte may have a role to protect from the induction of inflammation leading to demyelination in CNS at early phase of EAE. Moreover, FABP7 may be involved in the regulation of fibronectin production through the modification of astrocyte activation at late phase of EAE.

  35. The TNF-TNFR Family of Co-signal Molecules. Peer-reviewed

    So T, Ishii N

    Advances in experimental medicine and biology　1189　53-84　2019

    DOI： 10.1007/978-981-32-9717-3_3 　

    ISSN： 0065-2598

  36. IQGAP1 restrains T cell cosignaling mediated by OX40 Peer-reviewed

    Okuyama Y, Nagashima H, Ushio-Fukai M, Croft M, Ishii N, So T

    FASEB J　34　540-554　2019

  37. TRAF5 promotes plasmacytoid dendritic cell development from bone marrow progenitors. Peer-reviewed

    Kobayashi S, Shiota Y, Kawabe T, Phung HT, Maruyama T, Owada Y, So T, Ishii N

    Biochem Biophys Res Commun　521　(2)　353-359　2019

  38. Bmi1 Regulates IκBα Degradation via Association with the SCF Complex. International-journal Peer-reviewed

    Okuyama Y, Tanaka Y, Jiang JJ, Kamimura D, Nakamura A, Ota M, Ohki T, Higo D, Ogura H, Ishii N, Atsumi T, Murakami M

    Journal of immunology (Baltimore, Md. : 1950)　201　(8)　2264-2272　2018/10

    DOI： 10.4049/jimmunol.1701223 　

    ISSN： 0022-1767

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    Bmi1 is a polycomb group protein and regulator that stabilizes the ubiquitination complex PRC1 in the nucleus with no evidently direct link to the NF-κB pathway. In this study, we report a novel function of Bmi1: its regulation of IκBα ubiquitination in the cytoplasm. A deficiency of Bmi1 inhibited NF-κB-mediated gene expression in vitro and a NF-κB-mediated mouse model of arthritis in vivo. Mechanistic analysis showed that Bmi1 associated with the SCF ubiquitination complex via its N terminus and with phosphorylation by an IKKα/β-dependent pathway, leading to the ubiquitination of IκBα. These effects on NF-κB-related inflammation suggest Bmi1 in the SCF complex is a potential therapeutic target for various diseases and disorders, including autoimmune diseases.

  39. 東北大学医学部における留年者の原因とアウトカム 過去35年間の卒業生へのアンケート結果

    亀岡 淳一, 石井 直人, 内海 衣恵, 石井 誠一, 大野 勲, 加賀谷 豊

    医学教育　49　(Suppl.)　126-126　2018/07

    Publisher: (一社)日本医学教育学会

    ISSN： 0386-9644

  40. OX40 costimulation inhibits Foxp3 expression and Treg induction via BATF3-dependent and independent mechanisms Peer-reviewed

    Zhang X, Xiao X, Lan P, Li J, Dou Y, Chen W, Ishii N, Chen S, Xia B, Chen K, Taparowsky E, Li XC

    Cell Report　24　(3)　607-618　2018/07

    DOI： 10.1016/j.celrep.2018.06.052 　

  41. TNF receptor associated factor 5 controls oncostatin M-mediated lung inflammation Peer-reviewed

    Tomoaki Machiyama, Takanori So, Yuko Okuyama, Shuhei Kobayashi, Hai The Phung, Atsuko Asao, Hideo Harigae, Naoto Ishii

    Biochemical and Biophysical Research Communications　499　(3)　544-550　2018/05/15

    Publisher: Elsevier B.V.

    DOI： 10.1016/j.bbrc.2018.03.186 　

    ISSN： 1090-2104 0006-291X

  42. GITR cosignal in ILC2s controls allergic lung inflammation. International-journal Peer-reviewed

    Hiroyuki Nagashima, Yuko Okuyama, Tsuyoshi Fujita, Takeo Takeda, Yasutaka Motomura, Kazuyo Moro, Takanori Hidaka, Koki Omori, Tsuyoshi Sakurai, Tomoaki Machiyama, Lishomwa C Ndhlovu, Carlo Riccardi, Takanori So, Naoto Ishii

    The Journal of allergy and clinical immunology　141　(5)　1939-1943　2018/05

    DOI： 10.1016/j.jaci.2018.01.028 　

    ISSN： 0091-6749

  43. TRAF2 and TRAF5 Associated with the Signal Transducing Receptor gp130 Limit IL-6-driven Transphosphorylation of JAK1 through the Inhibition of Proximal JAK-JAK Interaction. Peer-reviewed

    Kimura M, Nagashima H, Okuyama Y, Ishii N, So T

    International immunology　2018/04

    DOI： 10.1093/intimm/dxy029 　

    ISSN： 0953-8178

  44. Regulation of Interleukin-6 Receptor Signaling by TNF Receptor-Associated Factor 2 and 5 During Differentiation of Inflammatory CD4+ T Cells. Peer-reviewed

    Nagashima H, Ishii N, So T

    Frontiers in immunology　9　1986　2018

    DOI： 10.3389/fimmu.2018.01986 　

  45. Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis Peer-reviewed

    Risa Ebina-Shibuya, Mitsuyo Matsumoto, Makoto Kuwahara, Kyoung-Jin Jang, Manabu Sugai, Yoshiaki Ito, Ryo Funayama, Keiko Nakayama, Yuki Sato, Naoto Ishii, Yasunobu Okamura, Kengo Kinoshita, Kohei Kometani, Tomohiro Kurosaki, Akihiko Muto, Masakazu Ichinose, Masakatsu Yamashita, Kazuhiko Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY　292　(44)　18098-18112　2017/11

    DOI： 10.1074/jbc.M117.808535 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  46. TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury Peer-reviewed

    Peixiang Lan, Yihui Fan, Yue Zhao, Xiaohua Lou, Howard P. Monsour, Xiaolong Zhang, Yongwon Choi, Yaling Dou, Naoto Ishii, Rafik M. Ghobrial, Xiang Xiao, Xian Chang Li

    JOURNAL OF CLINICAL INVESTIGATION　127　(6)　2222-2234　2017/06

    DOI： 10.1172/JCI91075 　

    ISSN： 0021-9738

    eISSN： 1558-8238

  47. CD103(+)CD11b(-) salivary gland dendritic cells have antigen cross-presenting capacity Peer-reviewed

    Lu Lu, Yukinori Tanaka, Naoto Ishii, Takashi Sasano, Shunji Sugawara

    EUROPEAN JOURNAL OF IMMUNOLOGY　47　(2)　305-313　2017/02

    DOI： 10.1002/eji.201646631 　

    ISSN： 0014-2980

    eISSN： 1521-4141

  48. ER Stress Protein CHOP Mediates Insulin Resistance by Modulating Adipose Tissue Macrophage Polarity Peer-reviewed

    Toru Suzuki, Junhong Gao, Yasushi Ishigaki, Keiichi Kondo, Shojiro Sawada, Tomohito Izumi, Kenji Uno, Keizo Kaneko, Sohei Tsukita, Kei Takahashi, Atsuko Asao, Naoto Ishii, Junta Imai, Tetsuya Yamada, Seiichi Oyadomari, Hideki Katagiri

    CELL REPORTS　18　(8)　2045-2057　2017/02

    DOI： 10.1016/j.celrep.2017.01.076 　

    ISSN： 2211-1247

  49. Oral CD103(-) CD11b(+) classical dendritic cells present sublingual antigen and induce Foxp3(+) regulatory T cells in draining lymph nodes Peer-reviewed

    Y. Tanaka, H. Nagashima, K. Bando, L. Lu, A. Ozaki, Y. Morita, S. Fukumoto, N. Ishii, S. Sugawara

    MUCOSAL IMMUNOLOGY　10　(1)　79-90　2017/01

    DOI： 10.1038/mi.2016.46 　

    ISSN： 1933-0219

    eISSN： 1935-3456

  50. Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 (Ape1/Ref-1) Modulates Antigen Presenting Cell-mediated T Helper Cell Type 1 Responses Peer-reviewed

    Akhter N, Takeda Y, Nara H, Araki A, Ishii N, Asao N, Asao H

    J Biol Chem　2016/11/04

    DOI： 10.1074/jbc.M116.742353 　

    ISSN： 1083-351X

  51. Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1 (Ape1/Ref-1) Modulates Antigen Presenting Cell-mediated T Helper Cell Type 1 Responses Peer-reviewed

    Nasrin Akhter, Yuji Takeda, Hidetoshi Nara, Akemi Araki, Naoto Ishii, Naoki Asao, Hironobu Asao

    JOURNAL OF BIOLOGICAL CHEMISTRY　291　(45)　23672-23680　2016/11

    DOI： 10.1074/jbc.M116.742353 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  52. The Tohoku Medical Megabank Project: Design and Mission Peer-reviewed

    Shinichi Kuriyama, Nobuo Yaegashi, Fuji Nagami, Tomohiko Arai, Yoshio Kawaguchi, Noriko Osumi, Masaki Sakaida, Yoichi Suzuki, Keiko Nakayama, Hiroaki Hashizume, Gen Tamiya, Hiroshi Kawame, Kichiya Suzuki, Atsushi Hozawa, Naoki Nakaya, Masahiro Kikuya, Hirohito Metoki, Ichiro Tsuji, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Akito Tsuboi, Shinichi Egawa, Kiyoshi Ito, Koichi Chida, Tadashi Ishii, Hiroaki Tomita, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Seizo Koshiba, Kengo Kinoshita, Soichi Ogishima, Takako Takai-Igarashi, Teiji Tominaga, Osamu Tanabe, Noriaki Ohuchi, Toru Shimosegawa, Shigeo Kure, Hiroshi Tanaka, Sadayoshi Ito, Jiro Hitomi, Kozo Tanno, Motoyuki Nakamura, Kuniaki Ogasawara, Seiichiro Kobayashi, Kiyomi Sakata, Mamoru Satoh, Atsushi Shimizu, Makoto Sasaki, Ryujin Endo, Kenji Sobue, Masayuki Yamamoto

    JOURNAL OF EPIDEMIOLOGY　26　(9)　493-511　2016/09

    DOI： 10.2188/jea.JE20150268 　

    ISSN： 0917-5040

  53. Local convection-enhanced delivery of an anti-CD40 agonistic monoclonal antibody induces antitumor effects in mouse glioma models Peer-reviewed

    Takuhiro Shoji, Ryuta Saito, Masashi Chonan, Ichiyo Shibahara, Aya Sato, Masayuki Kanamori, Yukihiko Sonoda, Toru Kondo, Naoto Ishii, Teiji Tominaga

    NEURO-ONCOLOGY　18　(8)　1120-1128　2016/08

    DOI： 10.1093/neuonc/now023 　

    ISSN： 1522-8517

    eISSN： 1523-5866

  54. Mesenteric lymph nodes contribute to proinflammatory Th17-cell generation during inflammation of the small intestine in mice Peer-reviewed

    Takeshi Kawabe, Nobu Suzuki, Satoshi Yamaki, Shu-lan Sun, Atsuko Asao, Yuko Okuyama, Takanori So, Yoichiro Iwakura, Naoto Ishii

    EUROPEAN JOURNAL OF IMMUNOLOGY　46　(5)　1119-1131　2016/05

    DOI： 10.1002/eji.201545907 　

    ISSN： 0014-2980

    eISSN： 1521-4141

  55. TNFR-Associated Factors 2 and 5 Differentially Regulate the Instructive IL-6 Receptor Signaling Required for Th17 Development Peer-reviewed

    Hiroyuki Nagashima, Yuko Okuyama, Takaya Hayashi, Naoto Ishii, Takanori So

    JOURNAL OF IMMUNOLOGY　196　(10)　4082-4089　2016/05

    DOI： 10.4049/jimmunol.1501610 　

    ISSN： 0022-1767

    eISSN： 1550-6606

  56. OX40 ligand newly expressed on bronchiolar progenitors mediates influenza infection and further exacerbates pneumonia Peer-reviewed

    Taizou Hirano, Toshiaki Kikuchi, Naoki Tode, Arif Santoso, Mitsuhiro Yamada, Yoshiya Mitsuhashi, Riyo Komatsu, Takeshi Kawabe, Takeshi Tanimoto, Naoto Ishii, Yuetsu Tanaka, Hidekazu Nishimura, Toshihiro Nukiwa, Akira Watanabe, Masakazu Ichinose

    EMBO MOLECULAR MEDICINE　8　(4)　422-436　2016/04

    DOI： 10.15252/emmm.201506154 　

    ISSN： 1757-4676

    eISSN： 1757-4684

  57. A Combination of Mitochondrial Oxidative Stress and Excess Fat/Calorie Intake Accelerates Steatohepatitis by Enhancing Hepatic CC Chemokine Production in Mice Peer-reviewed

    Tadashi Moro, Sachie Nakao, Hideaki Sumiyoshi, Takamasa Ishii, Masaki Miyazawa, Naoaki Ishii, Tadayuki Sato, Yumi Iida, Yoshinori Okada, Masayuki Tanaka, Hideki Hayashi, Satoshi Ueha, Kouji Matsushima, Yutaka Inagaki

    PLOS ONE　11　(1)　e0146592　2016/01

    DOI： 10.1371/journal.pone.0146592 　

    ISSN： 1932-6203

  58. TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection Peer-reviewed

    Glen M. Chew, Tsuyoshi Fujita, Gabriela M. Webb, Benjamin J. Burwitz, Helen L. Wu, Jason S. Reed, Katherine B. Hammond, Kiera L. Clayton, Naoto Ishii, Mohamed Abdel-Mohsen, Teri Liegler, Brooks I. Mitchell, Frederick M. Hecht, Mario Ostrowski, Cecilia M. Shikuma, Scott G. Hansen, Mark Maurer, Alan J. Korman, Steven G. Deeks, Jonah B. Sacha, Lishomwa C. Ndhlovu

    PLOS PATHOGENS　12　(1)　e1005349　2016/01

    DOI： 10.1371/journal.ppat.1005349 　

    ISSN： 1553-7366

    eISSN： 1553-7374

  59. CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models Peer-reviewed

    Masashi Chonan, Ryuta Saito, Takuhiro Shoji, Ichiyo Shibahara, Masayuki Kanamori, Yukihiko Sonoda, Mika Watanabe, Toshiaki Kikuchi, Naoto Ishii, Teiji Tominaga

    NEURO-ONCOLOGY　17　(11)　1453-1462　2015/11

    DOI： 10.1093/neuonc/nov090 　

    ISSN： 1522-8517

    eISSN： 1523-5866

  60. OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy Peer-reviewed

    Ichiyo Shibahara, Ryuta Saito, Rong Zhang, Masashi Chonan, Takuhiro Shoji, Masayuki Kanamori, Yukihiko Sonoda, Toshihiro Kumabe, Masahiko Kanehira, Toshiaki Kikuchi, Takanori So, Takashi Watanabe, Hiroaki Takahashi, Erina Iwabuchi, Yuetsu Tanaka, Yukiko Shibahara, Hironobu Sasano, Naoto Ishii, Teiji Tominaga

    MOLECULAR CANCER　14　41　2015/02

    DOI： 10.1186/s12943-015-0307-3 　

    ISSN： 1476-4598

  61. 東北大学の災害医療教育

    江川新一, 佐々木宏之, 細井義夫, 服部俊夫, 石井正, 石井直人

    日本集団災害医学会誌　19　(3)　444-444　2014/12

    Publisher:

    ISSN： 1345-7047

  62. Expansion of Dysfunctional Tim-3-Expressing Effector Memory CD8(+) T Cells during Simian Immunodeficiency Virus Infection in Rhesus Macaques Peer-reviewed

    Tsuyoshi Fujita, Benjamin J. Burwitz, Glen M. Chew, Jason S. Reed, Reesab Pathak, Elizabeth Seger, Kiera L. Clayton, James M. Rini, Mario A. Ostrowski, Naoto Ishii, Marcelo J. Kuroda, Scott G. Hansen, Jonah B. Sacha, Lishomwa C. Ndhlovu

    JOURNAL OF IMMUNOLOGY　193　(11)　5576-5583　2014/12

    DOI： 10.4049/jimmunol.1400961 　

    ISSN： 0022-1767

    eISSN： 1550-6606

  63. Fluorescently Activated Cell Sorting Followed by Microarray Profiling of Helper T Cell Subtypes from Human Peripheral Blood Peer-reviewed

    Chiaki Ono, Zhiqian Yu, Yoshiyuki Kasahara, Yoshie Kikuchi, Naoto Ishii, Hiroaki Tomita

    PLOS ONE　9　(11)　e111405　2014/11

    DOI： 10.1371/journal.pone.0111405 　

    ISSN： 1932-6203

  64. OX40 and IL-7 play synergistic roles in the homeostatic proliferation of effector memory CD4(+) T cells Peer-reviewed

    Satoshi Yamaki, Shouji Ine, Takeshi Kawabe, Yuko Okuyama, Nobu Suzuki, Pejman Soroosh, Seyed Fazlollah Mousavi, Hiroyuki Nagashima, Shu-lan Sun, Takanori So, Takeshi Sasaki, Hideo Harigae, Kazuo Sugamura, Hironori Kudo, Motoshi Wada, Masaki Nio, Naoto Ishii

    EUROPEAN JOURNAL OF IMMUNOLOGY　44　(10)　3015-3025　2014/10

    DOI： 10.1002/eji.201444701 　

    ISSN： 0014-2980

    eISSN： 1521-4141

  65. Erratum: Activation of Notch1 promotes development of human CD8+ single positive T cells in humanized mice (Biochemical and Biophysical Research Communications (2014) 447 (346-351)) Peer-reviewed

    Yoichi Haji, Makiko Suzuki, Kunihiko Moriya, Takanori So, Katsuto Hozumi, Masamichi Mizuma, Michiaki Unno, Naoto Ishii

    Biochemical and Biophysical Research Communications　452　(1)　206-207　2014/09/12

    Publisher: Academic Press Inc.

    DOI： 10.1016/j.bbrc.2014.08.099 　

    ISSN： 1090-2104 0006-291X

  66. The adaptor TRAF5 limits the differentiation of inflammatory CD4(+) T cells by antagonizing signaling via the receptor for IL-6 Peer-reviewed

    Hiroyuki Nagashima, Yuko Okuyama, Atsuko Asao, Takeshi Kawabe, Satoshi Yamaki, Hiroyasu Nakano, Michael Croft, Naoto Ishii, Takanori So

    NATURE IMMUNOLOGY　15　(5)　449-+　2014/05

    DOI： 10.1038/ni.2863 　

    ISSN： 1529-2908

    eISSN： 1529-2916

  67. Activation of Notch1 promotes development of human CD8(+) single positive T cells in humanized mice Peer-reviewed

    Yoichi Haji, Makiko Suzuki, Kunihiko Moriya, Takanori So, Katsuto Hozumi, Masamichi Mizuma, Michiaki Unno, Naoto Ishii

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　447　(2)　346-351　2014/05

    DOI： 10.1016/j.bbrc.2014.04.003 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  68. OX40 ligand regulates splenic CD8(-) dendritic cell-induced Th2 responses in vivo Peer-reviewed

    Fumitaka Kamachi, Norihiro Harada, Yoshihiko Usui, Tamami Sakanishi, Naoto Ishii, Ko Okumura, Sachiko Miyake, Hisaya Akiba

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　444　(2)　235-240　2014/02

    DOI： 10.1016/j.bbrc.2014.01.060 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  69. Hepatocyte growth factor regulated tyrosine kinase substrate in the peripheral development and function of B-cells Peer-reviewed

    Takayuki Nagata, Kazuko Murata, Ryo Murata, Shu-lan Sun, Yutaro Saito, Shuhei Yamaga, Nobuyuki Tanaka, Keiichi Tamai, Kunihiko Moriya, Noriyuki Kasai, Kazuo Sugamura, Naoto Ishii

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　443　(2)　351-356　2014/01

    DOI： 10.1016/j.bbrc.2013.11.029 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  70. Gene Therapy Model of X-linked Severe Combined Immunodeficiency Using a Modified Foamy Virus Vector Peer-reviewed

    Satoshi Horino, Toru Uchiyama, Takanori So, Hiroyuki Nagashima, Shu-lan Sun, Miki Sato, Atsuko Asao, Yoichi Haji, Yoji Sasahara, Fabio Candotti, Shigeru Tsuchiya, Shigeo Kure, Kazuo Sugamura, Naoto Ishii

    PLOS ONE　8　(8)　e71594　2013/08

    DOI： 10.1371/journal.pone.0071594 　

    ISSN： 1932-6203

  71. Y chromosome-linked B and NK cell deficiency in mice Peer-reviewed

    Shu-Lan Sun, Satoshi Horino, Ari Itoh-Nakadai, Takeshi Kawabe, Atsuko Asao, Takeshi Takahashi, Takanori So, Ryo Funayama, Motonari Kondo, Hirotomo Saitsu, Naomichi Matsumoto, Keiko Nakayama, Naoto Ishii

    Journal of Immunology　190　(12)　6209-6220　2013/06/15

    DOI： 10.4049/jimmunol.1300303 　

    ISSN： 0022-1767 1550-6606

  72. Homeostatic Proliferation of Naive CD4+ T Cells in Mesenteric Lymph Nodes Generates Gut-Tropic Th17 Cells Peer-reviewed

    Takeshi Kawabe, Shu-lan Sun, Tsuyoshi Fujita, Satoshi Yamaki, Atsuko Asao, Takeshi Takahashi, Takanori So, Naoto Ishii

    JOURNAL OF IMMUNOLOGY　190　(11)　5788-5798　2013/06

    DOI： 10.4049/jimmunol.1203111 　

    ISSN： 0022-1767

  73. A Small Molecule Inhibitor to Plasminogen Activator Inhibitor 1 Inhibits Macrophage Migration Peer-reviewed

    Atsuhiko Ichimura, Sachiko Matsumoto, Shinobu Suzuki, Takashi Dan, Satoshi Yamaki, Yayoi Sato, Hideyasu Kiyomoto, Naoto Ishii, Kiyotaka Okada, Osamu Matsuo, Fan-Fan Hou, Douglas E. Vaughan, Charles van Ypersele de Strihou, Toshio Miyata

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　33　(5)　935-U165　2013/05

    DOI： 10.1161/ATVBAHA.113.301224 　

    ISSN： 1079-5642

  74. マウスB細胞機能制御における小胞輸送関連分子Hrsの関与

    永田 隆之, 石井 直人, 森谷 邦彦, 村田 亮, 村田 和子

    日本薬学会年会要旨集　133年会　(3)　142-142　2013/03

    Publisher: (公社)日本薬学会

    ISSN： 0918-9823

  75. PARADOXICAL EFFECTS OF ENDOGENOUS OX40 LIGAND IN GLIOMA TRIGGERED BY TUMOR HYPOXIA AND EFFECTIVE INDUCTION OF ANTI-CANCER IMMUNITY WITH OX40 VACCINATION THERAPY Peer-reviewed

    Ichiyo Shibahara, Ryuta Saito, Rong Zhang, Masayuki Kanamori, Yukihiko Sonoda, Toshihiro Kumabe, Toshiaki Kikuchi, Takanori So, Naoto Ishii, Teiji Tominaga

    NEURO-ONCOLOGY　14　39-39　2012/10

    ISSN： 1522-8517

  76. Development of a Multi-Step Leukemogenesis Model of MLL-Rearranged Leukemia Using Humanized Mice Peer-reviewed

    Kunihiko Moriya, Makiko Suzuki, Yohei Watanabe, Takeshi Takahashi, Yoko Aoki, Toru Uchiyama, Satoru Kumaki, Yoji Sasahara, Masayoshi Minegishi, Shigeo Kure, Shigeru Tsuchiya, Kazuo Sugamura, Naoto Ishii

    PLOS ONE　7　(6)　e37892-e37892　2012/06

    DOI： 10.1371/journal.pone.0037892 　

    ISSN： 1932-6203

  77. Runx1 Deficiency in CD4(+) T Cells Causes Fatal Autoimmune Inflammatory Lung Disease Due to Spontaneous Hyperactivation of Cells Peer-reviewed

    Won Fen Wong, Kazuyoshi Kohu, Akira Nakamura, Masahito Ebina, Toshiaki Kikuchi, Ryushi Tazawa, Keisuke Tanaka, Shunsuke Kon, Tomo Funaki, Akiko Sugahara-Tobinai, Chung Yeng Looi, Shota Endo, Ryo Funayama, Mineo Kurokawa, Sonoko Habu, Naoto Ishii, Manabu Fukumoto, Koh Nakata, Toshiyuki Takai, Masanobu Satake

    JOURNAL OF IMMUNOLOGY　188　(11)　5408-5420　2012/06

    DOI： 10.4049/jimmunol.1102991 　

    ISSN： 0022-1767

    eISSN： 1550-6606

  78. Potential utility of eGFP-expressing NOG mice (NOG-EGFP) as a high purity cancer sampling system Peer-reviewed

    Kentaro Shima, Masamichi Mizuma, Hiroki Hayashi, Kei Nakagawa, Takaho Okada, Naoaki Sakata, Noriyuki Omura, Yo Kitamura, Fuyuhiko Motoi, Toshiki Rikiyama, Yu Katayose, Shinichi Egawa, Naoto Ishii, Akira Horii, Michiaki Unno

    JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH　31　(1)　55-55　2012/06

    DOI： 10.1186/1756-9966-31-55 　

    ISSN： 1756-9966

  79. Induction of human humoral immune responses in a novel HLA-DR-expressing transgenic NOD/Shi-scid/gamma c(null) mouse Peer-reviewed

    Makiko Suzuki, Takeshi Takahashi, Ikumi Katano, Ryoji Ito, Mamoru Ito, Hideo Harigae, Naoto Ishii, Kazuo Sugamura

    INTERNATIONAL IMMUNOLOGY　24　(4)　243-252　2012/04

    DOI： 10.1093/intimm/dxs045 　

    ISSN： 0953-8178

  80. Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension Peer-reviewed

    Moloud Rabieyousefi, Pejman Soroosh, Kimio Satoh, Fumiko Date, Naoto Ishii, Masahiro Yamashita, Masahiko Oka, Ivan F. McMurtry, Hiroaki Shimokawa, Masato Nose, Kazuo Sugamura, Masao Ono

    BMC IMMUNOLOGY　12　67-67　2011/12

    DOI： 10.1186/1471-2172-12-67 　

    ISSN： 1471-2172

  81. ヒト免疫異常症とヒト化マウス HLA-DR発現NOGマウスを用いたヒト液性免疫の誘導(Induction of the humoral immune response in HLA-DR(0405) transgenic humanized NOG mouse)

    鈴木 真紀子, 高橋 武司, 森谷 邦彦, 石井 直人

    日本免疫学会総会・学術集会記録　40　47-47　2011/11

    Publisher: (NPO)日本免疫学会

    ISSN： 0919-1984

  82. Involvement of osteopontin and its signaling molecule CD44 in clinicopathological features of adult T cell leukemia Peer-reviewed

    Haorile Chagan-Yasutan, Kunihiro Tsukasaki, Yayoi Takahashi, Shigeru Oguma, Hideo Harigae, Naoto Ishii, Jing Zhang, Manabu Fukumoto, Toshio Hattori

    LEUKEMIA RESEARCH　35　(11)　1484-1490　2011/11

    DOI： 10.1016/j.leukres.2011.05.011 　

    ISSN： 0145-2126

  83. Natural killer (NK)-dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4(+) T cells Peer-reviewed

    Masafumi Nakayama, Kazuyoshi Takeda, Mitsuko Kawano, Toshiyuki Takai, Naoto Ishii, Kouetsu Ogasawara

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　108　(45)　18360-18365　2011/11

    DOI： 10.1073/pnas.1110584108 　

    ISSN： 0027-8424

  84. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. International-journal Peer-reviewed

    Fumiaki Kamada, Yoko Aoki, Ayumi Narisawa, Yu Abe, Shoko Komatsuzaki, Atsuo Kikuchi, Junko Kanno, Tetsuya Niihori, Masao Ono, Naoto Ishii, Yuji Owada, Miki Fujimura, Yoichi Mashimo, Yoichi Suzuki, Akira Hata, Shigeru Tsuchiya, Teiji Tominaga, Yoichi Matsubara, Shigeo Kure

    Journal of human genetics　56　(1)　34-40　2011/01

    DOI： 10.1038/jhg.2010.132 　

    More details Close

    Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although ∼ 15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P = 5.3 × 10(-10)). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P = 1.2 × 10(-43), odds ratio = 190.8, 95% confidence interval = 71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

  85. OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization Peer-reviewed

    Makoto Nakano, Yoshihiro Fukumoto, Kimio Satoh, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    CARDIOVASCULAR RESEARCH　88　(3)　539-546　2010/12

    DOI： 10.1093/cvr/cvq211 　

    ISSN： 0008-6363

  86. Characterization of the epithelial cell adhesion molecule (EpCAM) plus cell population in hepatocellular carcinoma cell lines Peer-reviewed

    Osamu Kimura, Takeshi Takahashi, Naoto Ishii, Yuki Inoue, Yoshiyuki Ueno, Takayuki Kogure, Koji Fukushima, Masaaki Shiina, Yoko Yamagiwa, Yasuteru Kondo, Jun Inoue, Eiji Kakazu, Takao Iwasaki, Naoki Kawagishi, Tooru Shimosegawa, Kazuo Sugamura

    CANCER SCIENCE　101　(10)　2145-2155　2010/10

    DOI： 10.1111/j.1349-7006.2010.01661.x 　

    ISSN： 1347-9032

  87. 統合失調症罹患者のTh1およびTh2細胞のマイクロアレイ遺伝子発現プロファイリング

    小野 千晶, 兪 志前, 田邊 陽一郎, 小松 浩, 松岡 洋夫, 曽良 一郎, 石井 直人, 富田 博秋

    日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集　20回・40回　151-151　2010/09

    Publisher: 日本臨床精神神経薬理学会・日本神経精神薬理学会

  88. In vivo assay of human NK-dependent ADCC using NOD/SCID/gamma c(null) (NOG) mice Peer-reviewed

    Miho Shiokawa, Takeshi Takahashi, Akihiro Murakami, Shoichi Kita, Mamoru Ito, Kazuo Sugamura, Naoto Ishii

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　399　(4)　733-737　2010/09

    DOI： 10.1016/j.bbrc.2010.07.145 　

    ISSN： 0006-291X

  89. Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice Peer-reviewed

    Tomoko Shima, Yasushi Sasaki, Mika Itoh, Akitoshi Nakashima, Naoto Ishii, Kazuo Sugamura, Shigeru Saito

    JOURNAL OF REPRODUCTIVE IMMUNOLOGY　85　(2)　121-129　2010/06

    DOI： 10.1016/j.jri.2010.02.006 　

    ISSN： 0165-0378

  90. Serial OX40 Engagement on CD4(+) T Cells and Natural Killer T Cells Causes Allergic Airway Inflammation Peer-reviewed

    Triya Damayanti, Toshiaki Kikuchi, Jamal Zaini, Hisayoshi Daito, Masahiko Kanehira, Kazuyoshi Kohu, Naoto Ishii, Masanobu Satake, Kazuo Sugamura, Toshihiro Nukiwa

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE　181　(7)　688-698　2010/04

    DOI： 10.1164/rccm.200910-1598OC 　

    ISSN： 1073-449X

  91. Early production of tumor necrosis factor-alpha by Gr-1+cells and its role in the host defense to pneumococcal infection in lungs Peer-reviewed

    Masumitsu Hatta, Natsuo Yamamoto, Akiko Miyazato, Naoto Ishii, Kiwamu Nakamura, Ken Inden, Tetsuji Aoyagi, Hiroyuki Kunishima, Yoichi Hirakata, Kazuo Suzuki, Mitsuo Kaku, Kazuyoshi Kawakami

    FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY　58　(2)　182-192　2010/03

    DOI： 10.1111/j.1574-695X.2009.00616.x 　

    ISSN： 0928-8244

  92. The analysis of the functions of human B and T cells in humanized NOD/shi-scid/gamma c(null) (NOG) mice (hu-HSC NOG mice) Peer-reviewed

    Yohei Watanabe, Takeshi Takahashi, Akira Okajima, Miho Shiokawa, Naoto Ishii, Ikumi Katano, Ryoji Ito, Mamoru Ito, Masayoshi Minegishi, Naoko Minegishi, Shigeru Tsuchiya, Kazuo Sugamura

    INTERNATIONAL IMMUNOLOGY　21　(7)　843-858　2009/07

    DOI： 10.1093/intimm/dxp050 　

    ISSN： 0953-8178

    eISSN： 1460-2377

  93. Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1 Peer-reviewed

    Kimio Satoh, Yoshihiro Fukumoto, Makoto Nakano, Koichiro Sugimura, Jun Nawata, Jun Demachi, Akihiko Karibe, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    CARDIOVASCULAR RESEARCH　81　(1)　226-234　2009/01

    DOI： 10.1093/cvr/cvn244 　

    ISSN： 0008-6363

  94. OX40 Costimulatory Signals Potentiate the Memory Commitment of Effector CD8(+) T Cells Peer-reviewed

    Seyed Fazlollah Mousavi, Pejman Soroosh, Takeshi Takahashi, Yasunobu Yoshikai, Hao Shen, Leo Lefrancois, Jannie Borst, Kazuo Sugamura, Naoto Ishii

    JOURNAL OF IMMUNOLOGY　181　(9)　5990-6001　2008/11

    ISSN： 0022-1767

  95. ATP drives lamina propria T(H)17 cell differentiation Peer-reviewed

    Koji Atarashi, Junichi Nishimura, Tatsuichiro Shima, Yoshinori Umesaki, Masahiro Yamamoto, Masaharu Onoue, Hideo Yagita, Naoto Ishii, Richard Evans, Kenya Honda, Kiyoshi Takeda

    NATURE　455　(7214)　808-U10　2008/10

    DOI： 10.1038/nature07240 　

    ISSN： 0028-0836

  96. OX40/OX40L costimulation affects induction of Foxp(3+) regulatory T cells in part by expanding memory T cells in vivo Peer-reviewed

    Xiang Xiao, Alexander Kroemer, Wenda Gao, Naoto Ishii, Gulcin Demirci, Xian Chang Li

    JOURNAL OF IMMUNOLOGY　181　(5)　3193-3201　2008/09

    ISSN： 0022-1767

  97. c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130 Peer-reviewed

    Yoshinori Tanaka, Nobuyuki Tanaka, Yasushi Saeki, Keiji Tanaka, Masaaki Murakami, Toshio Hirano, Naoto Ishii, Kazuo Sugamura

    MOLECULAR AND CELLULAR BIOLOGY　28　(15)　4805-4818　2008/08

    DOI： 10.1128/MCB.01784-07 　

    ISSN： 0270-7306

  98. Co-inhibitory roles for glucocorticoid-induced TNF receptor in CD1d-dependent natural killer T cells Peer-reviewed

    Shuming Chen, Lishomwa C. Ndhlovu, Takeshi Takahashi, Kazuyoshi Takeda, Yoshinori Ikarashi, Toshiaki Kikuchi, Kazuko Murata, Pier Paolo Pandolfi, Carlo Riccardi, Masao Ono, Kazuo Sugamura, Naoto Ishii

    EUROPEAN JOURNAL OF IMMUNOLOGY　38　(8)　2229-2240　2008/08

    DOI： 10.1002/eji.200838167 　

    ISSN： 0014-2980

  99. Mannose-binding lectin (MBL)-associated serine protease (MASP)-1 contributes to activation of the lectin complement pathway Peer-reviewed

    Minoru Takahashi, Daisuke Iwaki, Kazuko Kanno, Yumi Ishida, Jie Xiong, Misao Matsushita, Yuichi Endo, Shigeto Miura, Naoto Ishii, Kazuo Sugamura, Teizo Fujita

    JOURNAL OF IMMUNOLOGY　180　(9)　6132-6138　2008/05

    ISSN： 0022-1767

  100. OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice Peer-reviewed

    Jamal Zaini, Sita Andarini, Minoru Tahara, Yasuo Saijo, Naoto Ishii, Kazuyoshi Kawakami, Masaru Taniguchi, Kazuo Sugamura, Toshihiro Nukiwa, Toshiaki Kikuchi

    JOURNAL OF CLINICAL INVESTIGATION　117　(11)　3330-3338　2007/11

    DOI： 10.1172/JCI32693 　

    ISSN： 0021-9738

  101. Human CD4(+) central and effector memory T cells produce IL-21: effect on cytokine-driven proliferation of CD4(+) T cell subsets Peer-reviewed

    Tadashi Onoda, Mizanur Rahman, Hidetoshi Nara, Akemi Araki, Koki Makabe, Kouhei Tsumoto, Izumi Kumagai, Toshio Kudo, Naoto Ishii, Nobuyuki Tanaka, Kazuo Sugamura, Kiyoshi Hayasaka, Hironobu Asao

    INTERNATIONAL IMMUNOLOGY　19　(10)　1191-1199　2007/10

    DOI： 10.1093/intimm/dxm090 　

    ISSN： 0953-8178

    eISSN： 1460-2377

  102. OX40 costimulation turns off Foxp3(+) tregs Peer-reviewed

    Minh Diem Vu, Xiang Xiao, Wenda Gao, Nicolas Degauque, Ming Chen, Alexander Kroemer, Nigel Killeen, Naoto Ishii, Xian Chang Li

    BLOOD　110　(7)　2501-2510　2007/10

    DOI： 10.1182/blood-2007-01-070748 　

    ISSN： 0006-4971

  103. Differential requirements for OX40 signals on generation of effector and central memory CD4(+) T cells Peer-reviewed

    Pejman Soroosh, Shouji Ine, Kazuo Sugamura, Naoto Ishii

    JOURNAL OF IMMUNOLOGY　179　(8)　5014-5023　2007/10

    ISSN： 0022-1767

  104. Dendritic cell expression of OX40 ligand acts as a costimulatory, not polarizing, signal for optimal th2 priming and memory induction in vivo Peer-reviewed

    Stephen J. Jenkins, Georgia Perona-Wright, Alan G. F. Worsley, Naoto Ishii, Andrew S. MacDonald

    JOURNAL OF IMMUNOLOGY　179　(6)　3515-3523　2007/09

    ISSN： 0022-1767

  105. Inhibition of tumor growth and metastasis by depletion of vesicular sorting protein Hrs: Its regulatory role on E-cadherin and beta-catenin Peer-reviewed

    Masafumi Toyoshima, Nobuyuki Tanaka, Jun Aoki, Yoshinori Tanaka, Kazuko Murata, Masanao Kyuuma, Hideyuki Kobayashi, Naoto Ishii, Nobuo Yaegashi, Kazuo Sugamura

    CANCER RESEARCH　67　(11)　5162-5171　2007/06

    DOI： 10.1158/0008-5472.CAN-06-2756 　

    ISSN： 0008-5472

  106. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice Peer-reviewed

    Makoto Nakano, Kimio Satoh, Yoshihiro Fukumoto, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    CIRCULATION RESEARCH　100　(5)　662-669　2007/03

    DOI： 10.1161/01.RES.0000260179.43672.fe 　

    ISSN： 0009-7330

  107. Establisbment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica Peer-reviewed

    Toshiyuki Takahashi, Kazuo Fujihara, Ichiro Nakashima, Tatsuro Misu, Isabelle Miyazawa, Masashi Nakamura, Shohei Watanabe, Naoto Ishii, Yasuto Itoyama

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　210　(4)　307-313　2006/12

    DOI： 10.1620/tjem.210.307 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  108. OX40-OX40 ligand interaction through T cell-T cell contact contributes to CD4 T cell longevity Peer-reviewed

    P Soroosh, S Ine, K Sugamura, N Ishii

    JOURNAL OF IMMUNOLOGY　176　(10)　5975-5987　2006/05

    ISSN： 0022-1767

  109. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice Peer-reviewed

    K Satoh, Y Kagaya, M Nakano, Y Ito, J Ohta, H Tada, A Karibe, N Minegishi, N Suzuki, M Yamamoto, M Ono, J Watanabe, K Shirato, N Ishii, K Sugamura, H Shimokawa

    CIRCULATION　113　(11)　1442-1450　2006/03

    DOI： 10.1161/CIRCULATIONAHA.105.583732 　

    ISSN： 0009-7322

  110. Regulatory T cell-like activity of Foxp3(+) adult T cell leukemia cells Peer-reviewed

    SM Chen, N Ishii, S Ine, S Ikeda, T Fujimura, LC Ndhlovu, P Soroosh, K Tada, H Harigae, J Kameoka, N Kasai, T Sasaki, K Sugamura

    INTERNATIONAL IMMUNOLOGY　18　(2)　269-277　2006/02

    DOI： 10.1093/intimm/dxh366 　

    ISSN： 0953-8178

  111. A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Fas(lpr) lupus mice Peer-reviewed

    H Komori, H Furukawa, S Mori, MR Ito, M Terada, MC Zhang, N Ishii, N Sakuma, M Nose, M Ono

    JOURNAL OF IMMUNOLOGY　176　(1)　395-400　2006/01

    ISSN： 0022-1767

  112. During viral infection of the respiratory tract, CD27, 4-1BB, and OX40 collectively determine formation of CD8(+) memory T cells and their capacity for secondary expansion Peer-reviewed

    J Hendriks, YL Xiao, JWA Rossen, KF van der Sluijs, K Sugamura, N Ishii, J Borst

    JOURNAL OF IMMUNOLOGY　175　(3)　1665-1676　2005/08

    ISSN： 0022-1767

  113. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility Peer-reviewed

    XS Wang, M Ria, PM Kelmenson, P Eriksson, DC Higgins, C Samnegard, C Petros, J Rollins, AM Bennet, B Wiman, U de Faire, C Wennberg, PG Olsson, N Ishii, K Sugamura, A Hamsten, K Forsman-Semb, J Lagercrantz, B Paigen

    NATURE GENETICS　37　(4)　365-372　2005/04

    DOI： 10.1038/ng1524 　

    ISSN： 1061-4036

  114. Hrs, a mammalian master molecule in vesicular transport and protein sorting, suppresses the degradation of ESCRT proteins signal transducing adaptor molecule 1 and 2 Peer-reviewed

    H Kobayashi, N Tanaka, H Asao, S Miura, M Kyuuma, K Semura, N Ishii, K Sugamura

    JOURNAL OF BIOLOGICAL CHEMISTRY　280　(11)　10468-10477　2005/03

    DOI： 10.1074/jbc.M409969200 　

    ISSN： 0021-9258

  115. T-Cell-depleted CD34+ cell transplantation from an HLA-mismatched donor in a low-birthweight infant with X-linked severe combined immunodeficiency Peer-reviewed

    A Nomura, H Takada, S Ohga, N Ishii, T Inoue, T Hara

    JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY　27　(2)　80-84　2005/02

    DOI： 10.1097/01.mph.0000152859.59880.54 　

    ISSN： 1077-4114

  116. TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice Peer-reviewed

    R Horai, A Nakajima, K Habiro, M Kotani, S Nakae, T Matsuki, A Nambu, S Saijo, H Kotaki, K Sudo, A Okahara, H Tanioka, T Ikuse, N Ishii, PL Schwartzberg, R Abe, Y Iwakura

    JOURNAL OF CLINICAL INVESTIGATION　114　(11)　1603-1611　2004/12

    DOI： 10.1172/JCI200420742 　

    ISSN： 0021-9738

  117. Essential role of OX40L on B cells in persistent alloantibody production following repeated alloimmunizations Peer-reviewed

    H Kato, H Kojima, N Ishii, H Hase, Y Imai, T Fujibayashi, K Sugamura, T Kobata

    JOURNAL OF CLINICAL IMMUNOLOGY　24　(3)　237-248　2004/05

    DOI： 10.1023/B:JOCI.0000025445.21894.e5 　

    ISSN： 0271-9142

  118. Adenovirus vector-mediated in vivo gene transfer of OX40 ligand to tumor cells enhances antitumor immunity of tumor-bearing hosts Peer-reviewed

    S Andarini, T Kikuchi, M Nukiwa, P Pradono, T Suzuki, S Ohkouchi, A Inoue, M Maemondo, N Ishii, Y Saijo, K Sugamura, T Nukiwa

    CANCER RESEARCH　64　(9)　3281-3287　2004/05

    DOI： 10.1158/0008-5472.CAN-03-3911 　

    ISSN： 0008-5472

  119. Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells Peer-reviewed

    Takeda, I, S Ine, N Killeen, LC Ndhlovu, K Murata, S Satomi, K Sugamura, N Ishii

    JOURNAL OF IMMUNOLOGY　172　(6)　3580-3589　2004/03

    ISSN： 0022-1767

  120. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis Peer-reviewed

    J Feng, T Misu, K Fujihara, S Sakoda, Y Nakatsuji, H Fukaura, S Kikuchi, K Tashiro, A Suzumura, N Ishii, K Sugamura, Nakashima, I, Y Itoyama

    MULTIPLE SCLEROSIS　10　(5)　494-498　2004

    DOI： 10.1191/1352458504ms1070oa 　

    ISSN： 1352-4585

  121. Effects of deficiencies of STAMs and Hrs, mammalian class E Vps proteins, on receptor downregulation Peer-reviewed

    C Kanazawa, E Morita, M Yamada, N Ishii, S Miura, H Asao, T Yoshimori, K Sugamura

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　309　(4)　848-856　2003/10

    DOI： 10.1016/j.bbrc.2003.08.078 　

    ISSN： 0006-291X

  122. OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses Peer-reviewed

    N Ishii, LC Ndhlovu, K Murata, T Sato, M Kamanaka, K Sugamura

    EUROPEAN JOURNAL OF IMMUNOLOGY　33　(9)　2372-2381　2003/09

    DOI： 10.1002/eji.200324031 　

    ISSN： 0014-2980

  123. Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif Peer-reviewed

    K Kikuchi, N Ishii, H Asao, K Sugamura

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　306　(3)　637-643　2003/07

    DOI： 10.1061/S0006-291x(03)01009-X 　

    ISSN： 0006-291X

  124. Critical role for OX40 ligand in the development of pathogenic Th2 cells in a murine model of asthma Peer-reviewed

    A Hoshino, Y Tanaka, H Akiba, Y Asakura, Y Mita, T Sakurai, A Takaoka, S Nakaike, N Ishii, K Sugamura, H Yagita, K Okumura

    EUROPEAN JOURNAL OF IMMUNOLOGY　33　(4)　861-869　2003/04

    DOI： 10.1002/eji.200323455 　

    ISSN： 0014-2980

  125. Signal-transducing adaptor molecules STAM1 and STAM2 are required for T-Cell development and survival Peer-reviewed

    M Yamada, N Ishii, H Asao, K Murata, C Kanazawa, H Sasaki, K Sugamura

    MOLECULAR AND CELLULAR BIOLOGY　22　(24)　8648-8658　2002/12

    DOI： 10.1128/MCB.22.24.8648-8658.2002 　

    ISSN： 0270-7306

  126. Consequences of OX40-OX40 ligand interactions in Langerhans cell function: enhanced contact hypersensitivity responses in OX40L-transgenic mice Peer-reviewed

    T Sato, N Ishii, K Murata, K Kikuchi, S Nakagawa, LC Ndhlovu, K Sugamura

    EUROPEAN JOURNAL OF IMMUNOLOGY　32　(11)　3326-3335　2002/11

    DOI： 10.1002/1521-4141(200211)32:11<3326::AID-IMMU3326>3.0.CO;2-9 　

    ISSN： 0014-2980

  127. Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases Peer-reviewed

    K Murata, M Nose, LC Ndhlovu, T Sato, K Sugamura, N Ishii

    JOURNAL OF IMMUNOLOGY　169　(8)　4628-4636　2002/10

    ISSN： 0022-1767

  128. The role of common gamma chain in human monocytes in vivo; evaluation from the studies of X-linked severe combined immunodeficiency (X-SCID) carriers and X-SCID patients who underwent cord blood stem cell transplantation Peer-reviewed

    T Ariga, K Yamaguchi, J Yoshida, A Miyanoshita, T Watanabe, T Date, J Miura, S Kumaki, N Ishii, Y Sakiyama

    BRITISH JOURNAL OF HAEMATOLOGY　118　(3)　858-863　2002/09

    DOI： 10.1046/j.1365-2141.2002.03679.x 　

    ISSN： 0007-1048

  129. Roles of DNA-dependent protein kinase and ATM in cell-cycle-dependent radiation sensitivity in human cells Peer-reviewed

    M Yoshida, Y Hosoi, H Miyachi, N Ishii, Y Matsumoto, A Enomoto, K Nakagawa, S Yamada, N Suzuki, T Ono

    INTERNATIONAL JOURNAL OF RADIATION BIOLOGY　78　(6)　503-512　2002/06

    DOI： 10.1080/09553000210123685 　

    ISSN： 0955-3002

  130. A transgenic mouse model for non-immune hydrops fetalis induced by the NS1 gene of human parvovirus B19 Peer-reviewed

    H Chisaka, E Morita, K Murata, N Ishii, N Yaegashi, K Okamura, K Sugamura

    JOURNAL OF GENERAL VIROLOGY　83　(Pt 2)　273-281　2002/02

    ISSN： 0022-1317

  131. Expression of OX40 in muscles of polymyositis and granulomatous myopathy Peer-reviewed

    M Tateyama, K Fujihara, N Ishii, K Sugamura, Y Onodera, Y Itoyama

    JOURNAL OF THE NEUROLOGICAL SCIENCES　194　(1)　29-34　2002/02

    DOI： 10.1016/S0022-510X(01)00668-2 　

    ISSN： 0022-510X

  132. Loss of neurons in the hippocampus and cerebral cortex of AMSH-deficient mice Peer-reviewed

    N Ishii, Y Owada, M Yamada, S Miura, K Murata, H Asao, H Kondo, K Sugamura

    MOLECULAR AND CELLULAR BIOLOGY　21　(24)　8626-8637　2001/12

    DOI： 10.1128/MCB.21.24.8626-8637.2001 　

    ISSN： 0270-7306

  133. Critical involvement of OX40 ligand signals in the T cell priming events during experimental autoimmune encephalomyelitis Peer-reviewed

    LC Ndhlovu, N Ishii, K Murata, T Sato, K Sugamura

    JOURNAL OF IMMUNOLOGY　167　(5)　2991-2999　2001/09

    ISSN： 0022-1767

  134. Cutting edge: The common gamma-chain is an indispensable subunit of the IL-21 receptor complex Peer-reviewed

    H Asao, C Okuyama, S Kumaki, N Ishii, S Tsuchiya, D Foster, K Sugamura

    JOURNAL OF IMMUNOLOGY　167　(1)　1-5　2001/07

    ISSN： 0022-1767

  135. Suppression of thymic development by the dominant-negative form of Gads Peer-reviewed

    K Kikuchi, Y Kawasaki, N Ishii, Y Sasaki, T Asao, T Takeshita, Miyoshi, I, N Kasai, K Sugamura

    INTERNATIONAL IMMUNOLOGY　13　(6)　777-783　2001/06

    DOI： 10.1093/intimm/13.6.777 　

    ISSN： 0953-8178

  136. Expression of gp34 (OX40 ligand) and OX40 on human T cell clones Peer-reviewed

    N Takasawa, N Ishii, N Higashimura, K Murata, Y Tanaka, M Nakamura, T Sasaki, K Sugamura

    JAPANESE JOURNAL OF CANCER RESEARCH　92　(4)　377-382　2001/04

    ISSN： 0910-5050

  137. Decreased expression of c-myc family genes in thymuses from myasthenia gravis patients Peer-reviewed

    T Nagata, H Onodera, M Ohuchi, Y Suzuki, H Tago, K Fujihara, N Ishii, K Sugamura, Y Shoji, M Handa, K Tabayashi, Y Itoyama

    JOURNAL OF NEUROIMMUNOLOGY　115　(1-2)　199-202　2001/04

    DOI： 10.1016/S0165-5728(01)00252-1 　

    ISSN： 0165-5728

  138. OX40/OX40L系のアレルギーの発症(B細胞の活性化とアレルギー)

    石井 直人, 村田 和子, 菅村 和夫

    アレルギー　50　(9)　846-846　2001

    Publisher: 一般社団法人 日本アレルギー学会

    DOI： 10.15036/arerugi.50.846_2 　

  139. STAM1/STAM2ダブルノックアウトマウスの作製とその解析 Peer-reviewed

    山田 充啓, 石井 直人, 村田 和子, 佐々木 義輝, 竹下 敏一, 菅村 和夫

    日本免疫学会総会・学術集会記録　30　222-222　2000/11

    Publisher: (NPO)日本免疫学会

    ISSN： 0919-1984

  140. Expression of OX40 and OX40 ligand (gp34) in the normal and myasthenic thymus Peer-reviewed

    J Onodera, T Nagata, K Fujihara, M Ohuchi, N Ishii, K Sugamura, Y Itoyama

    ACTA NEUROLOGICA SCANDINAVICA　102　(4)　236-243　2000/10

    DOI： 10.1034/j.1600-0404.2000.102004236.x 　

    ISSN： 0001-6314

  141. Characterization of the gamma c chain among 27 unrelated Japanese patients with X-linked severe combined immunodeficiency (X-SCID) Peer-reviewed

    S Kumaki, N Ishii, M Minegishi, Y Ohashi, Hakozaki, I, S Nonoyama, K Imai, T Morio, Tsuge, I, Y Sakiyama, A Miyanoshita, J Miura, M Mayumi, T Heike, K Katamura, H Takada, Izumi, I, J Kamizono, S Hibi, H Sasaki, M Kimura, A Kikuta, Y Date, M Sako, H Tanaka, K Sano, K Sugamura, S Tsuchiya

    HUMAN GENETICS　107　(4)　406-408　2000/10

    ISSN： 0340-6717

  142. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand Peer-reviewed

    K Murata, N Ishii, H Takano, S Miura, LC Ndhlovu, M Nose, T Noda, K Sugamura

    JOURNAL OF EXPERIMENTAL MEDICINE　191　(2)　365-374　2000/01

    DOI： 10.1084/jem.191.2.365 　

    ISSN： 0022-1007

  143. Grf40, a novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT Peer-reviewed

    H Asada, N Ishii, Y Sasaki, K Endo, H Kasai, N Tanaka, T Takeshita, S Tsuchiya, T Konno, K Sugamura

    JOURNAL OF EXPERIMENTAL MEDICINE　189　(9)　1383-1390　1999/05

    DOI： 10.1084/jem.189.9.1383 　

    ISSN： 0022-1007

  144. Functional role of interleukin-4 (IL-4) and IL-7 in the development of X-linked severe combined immunodeficiency Peer-reviewed

    S Kumaki, N Ishii, M Minegishi, S Tsuchiya, D Cosman, K Sugamura, T Konno

    BLOOD　93　(2)　607-612　1999/01

    ISSN： 0006-4971

  145. Prolongation of allograft survival by administration of mAb specific for the three subunits of IL-2 receptor Peer-reviewed

    K Yasuda, T Nemoto, Y Ohashi, S Satomi, K Murata, N Ishii, T Takeshita, K Sugamura

    INTERNATIONAL IMMUNOLOGY　10　(5)　561-567　1998/05

    DOI： 10.1093/intimm/10.5.561 　

    ISSN： 0953-8178

  146. X-linked severe combined immunodeficiency with gamma delta T cells Peer-reviewed

    EY Jung, T Heike, K Katamura, H Kimata, K Ohmori, Y Morikawa, N Ishii, M Mayumi

    ACTA PAEDIATRICA JAPONICA　39　(4)　442-447　1997/08

    ISSN： 0374-5600

  147. STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction Peer-reviewed

    T Takeshita, T Arita, M Higuchi, H Asao, K Endo, H Kuroda, N Tanaka, K Murata, N Ishii, K Sugamura

    IMMUNITY　6　(4)　449-457　1997/04

    ISSN： 1074-7613

  148. Functional expression on human trophoblasts of interleukin 4 and interleukin 7 receptor complexes with a common gamma chain Peer-reviewed

    S Saito, N Harada, N Ishii, T Morii, S Sakakura, M Enomoto, H Umekage, K Nishikawa, N Narita, M Nakamura, K Sugamura, H Morikawa

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　231　(2)　429-434　1997/02

    DOI： 10.1006/bbrc.1997.6121 　

    ISSN： 0006-291X

  149. X-linked severe combined immunodeficiency with γδT cells Peer-reviewed

    Eun-Young Jung, Toshio Heike, Kenji Katamura, Hajime Kimata, Katsuyuki Ohmori, Yoshiro Morikawa, Naoto Ishii, Mitsufumi Mayumi

    Pediatrics International　39　(4)　442-447　1997

    DOI： 10.1111/j.1442-200X.1997.tb03614.x 　

    ISSN： 1442-200X 1328-8067

  150. IL-2 receptor gamma chain expression on CD34 positive hematopoietic progenitor cells from bone marrow and cord blood Peer-reviewed

    M Itano, S Tsuchiya, S Morita, H Fujie, N Ishii, T Yanagisawa, Y Ohashi, M Minegishi, K Sugamura, T Konno

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　178　(4)　389-398　1996/04

    DOI： 10.1620/tjem.178.389 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  151. Expression of the interleukin-2 receptor gamma chain on cord blood mononuclear cells Peer-reviewed

    S Saito, T Morii, H Umekage, K Makita, K Nishikawa, N Narita, M Ichijo, H Morikawa, N Ishii, M Nakamura, K Sugamura

    BLOOD　87　(8)　3344-3350　1996/04

    ISSN： 0006-4971

  152. T cell reconstitution by haploidentical BMT does not restore the diversification of the Ig heavy chain gene in patients with X-linked SCID Peer-reviewed

    Y Minegishi, N Ishii, M Tsuchida, H Okawa, K Sugamura, J Yata

    BONE MARROW TRANSPLANTATION　16　(6)　801-806　1995/12

    ISSN： 0268-3369

  153. 3 NOVEL MUTATIONS IN THE INTERLEUKIN-2 RECEPTOR-GAMMA CHAIN GENE IN 4 JAPANESE PATIENTS WITH X-LINKED SEVERE COMBINED IMMUNODEFICIENCY Peer-reviewed

    Y MINEGISHI, N ISHII, H MAEDA, S TAKAGI, M TSUCHIDA, H OKAWA, K SUGAMURA, J YATA

    HUMAN GENETICS　96　(6)　681-683　1995/12

    DOI： 10.1007/BF00210299 　

    ISSN： 0340-6717

  154. DIFFERENCES IN THE INTERLEUKIN-2 (IL-2) RECEPTOR SYSTEM IN HUMAN AND MOUSE - ALPHA-CHAIN IS REQUIRED FOR FORMATION OF THE FUNCTIONAL-MOUSE IL-2 RECEPTOR Peer-reviewed

    T NEMOTO, T TAKESHITA, N ISHII, M KONDO, M HIGUCHI, S SATOMI, M NAKAMURA, S MORI, K SUGAMURA

    EUROPEAN JOURNAL OF IMMUNOLOGY　25　(11)　3001-3005　1995/11

    ISSN： 0014-2980

  155. FUNCTIONAL-ANALYSIS OF THE HUMAN INTERLEUKIN-2 RECEPTOR-GAMMA CHAIN GENE PROMOTER Peer-reviewed

    K OHBO, N TAKASAWA, N ISHII, N TANAKA, M NAKAMURA, K SUGAMURA

    JOURNAL OF BIOLOGICAL CHEMISTRY　270　(13)　7479-7486　1995/03

    DOI： 10.1074/jbc.270.13.7479 　

    ISSN： 0021-9258

  156. SHARING OF THE IL-2 RECEPTOR-GAMMA CHAIN WITH THE FUNCTIONAL IL-9 RECEPTOR COMPLEX Peer-reviewed

    Y KIMURA, T TAKESHITA, M KONDO, N ISHII, M NAKAMURA, J VANSNICK, K SUGAMURA

    INTERNATIONAL IMMUNOLOGY　7　(1)　115-120　1995/01

    DOI： 10.1093/intimm/7.1.115 　

    ISSN： 0953-8178

  157. INTERLEUKIN 2-INDUCED ACTIVATION OF JAK3 - POSSIBLE INVOLVEMENT IN SIGNAL-TRANSDUCTION FOR C-MYC INDUCTION AND CELL-PROLIFERATION Peer-reviewed

    H ASAO, N TANAKA, N ISHII, M HIGUCHI, T TAKESHITA, M NAKAMURA, T SHIRASAWA, K SUGAMURA

    FEBS LETTERS　351　(2)　201-206　1994/09

    DOI： 10.1016/0014-5793(94)00831-0 　

    ISSN： 0014-5793

  158. EXPRESSION OF THE IL-2 RECEPTOR-GAMMA CHAIN ON VARIOUS POPULATIONS IN HUMAN PERIPHERAL-BLOOD Peer-reviewed

    N ISHII, T TAKESHITA, Y KIMURA, K TADA, M KONDO, M NAKAMURA, K SUGAMURA

    INTERNATIONAL IMMUNOLOGY　6　(8)　1273-1277　1994/08

    DOI： 10.1093/intimm/6.8.1273 　

    ISSN： 0953-8178

  159. IMPAIRMENT OF LIGAND-BINDING AND GROWTH SIGNALING OF MUTANT IL-2 RECEPTOR GAMMA-CHAINS IN PATIENTS WITH X-LINKED SEVERE COMBINED IMMUNODEFICIENCY Peer-reviewed

    N ISHII, H ASAO, Y KIMURA, T TAKESHITA, M NAKAMURA, S TSUCHIYA, T KONNO, M MAEDA, T UCHIYAMA, K SUGAMURA

    JOURNAL OF IMMUNOLOGY　153　(3)　1310-1317　1994/08

    ISSN： 0022-1767

  160. PHYSICAL ASSOCIATION OF JAK1 AND JAK2 TYROSINE KINASES WITH THE INTERLEUKIN-2 RECEPTOR-BETA AND GAMMA-CHAINS Peer-reviewed

    N TANAKA, H ASAO, K OHBO, N ISHII, T TAKESHITA, M NAKAMURA, H SASAKI, K SUGAMURA

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　91　(15)　7271-7275　1994/07

    DOI： 10.1073/pnas.91.15.7271 　

    ISSN： 0027-8424

  161. SHARING OF THE INTERLEUKIN-2 (IL-2) RECEPTOR GAMMA-CHAIN BETWEEN RECEPTORS FOR IL-2 AND IL-4 Peer-reviewed

    M KONDO, T TAKESHITA, N ISHII, M NAKAMURA, S WATANABE, K ARAI, K SUGAMURA

    SCIENCE　262　(5141)　1874-1877　1993/12

    DOI： 10.1126/science.8266076 　

    ISSN： 0036-8075

  162. KINETIC-STUDY OF INTERLEUKIN-2 BINDING ON THE RECONSTITUTED INTERLEUKIN-2 RECEPTOR COMPLEXES INCLUDING THE HUMAN GAMMA-CHAIN Peer-reviewed

    M MATSUOKA, T TAKESHITA, N ISHII, M NAKAMURA, T OHKUBO, K SUGAMURA

    EUROPEAN JOURNAL OF IMMUNOLOGY　23　(10)　2472-2476　1993/10

    DOI： 10.1002/eji.1830231014 　

    ISSN： 0014-2980

  163. RECONSTITUTION OF FUNCTIONAL INTERLEUKIN-2 RECEPTOR COMPLEXES ON FIBROBLASTOID CELLS - INVOLVEMENT OF THE CYTOPLASMIC DOMAIN OF THE GAMMA-CHAIN IN 2 DISTINCT SIGNALING PATHWAYS Peer-reviewed

    H ASAO, T TAKESHITA, N ISHII, S KUMAKI, M NAKAMURA, K SUGAMURA

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　90　(9)　4127-4131　1993/05

    DOI： 10.1073/pnas.90.9.4127 　

    ISSN： 0027-8424

  164. CLONING OF THE GAMMA-CHAIN OF THE HUMAN IL-2 RECEPTOR Peer-reviewed

    T TAKESHITA, H ASAO, K OHTANI, N ISHII, S KUMAKI, N TANAKA, H MUNAKATA, M NAKAMURA, K SUGAMURA

    SCIENCE　257　(5068)　379-382　1992/07

    DOI： 10.1126/science.1631559 　

    ISSN： 0036-8075

  165. Loss of hippocampal CA3 pyramidal neurons in mice lacking STAM1 Peer-reviewed

    Yamada, M, Takeshita, T, Miura, S, Murata, K, Kimura, Y, Ishii, N, Nose, M, Sakagami, H, Kondo, H, Tashiro, F, Miyazaki, J, Sasaki, H, Sugamura, K

    Mol Cell Biol　21　3807-3819

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    日本小児科学会雑誌　126　(2)　230-230　2022/02

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  2. Traf5-deficiency promotes T-helper cell type 1 development mediated by IL-27

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    日本生化学会大会プログラム・講演要旨集　94回　[P-890]　2021/11

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  4. Elucidation of regulatory mechanisms of IL-27 receptor signaling mediated by TRAF5 in CD4+ T cells

    河原永悟, 藤森由夏, 大石真結, 川口甲介, 守田雅志, 奥山祐子, 石井直人, 宗孝紀

    日本薬学会年会要旨集(Web)　141st　2021

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  5. Author Correction: Requirements for the differentiation of innate T-bethigh memory-phenotype CD4+ T lymphocytes under steady state (Nature Communications, (2020), 11, 1, (3366), 10.1038/s41467-020-17136-1)

    Takeshi Kawabe, Jaeu Yi, Akihisa Kawajiri, Kerry Hilligan, Difeng Fang, Naoto Ishii, Hidehiro Yamane, Jinfang Zhu, Dragana Jankovic, Kwang Soon Kim, Giorgio Trinchieri, Alan Sher

    Nature Communications　11　(1)　2020/12/01

    Publisher: Nature Research

    DOI： 10.1038/s41467-020-18568-5 　

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  6. サイトカイン受容体gp130とTRAFタンパク質の相互作用様式の解明

    藤森由夏, 河原永悟, 川口甲介, 守田雅志, 帯田孝之, 奥山祐子, 水口峰之, 石井直人, 宗孝紀

    日本薬学会北陸支部例会/日本病院薬剤師会北陸ブロック学術大会プログラム集&要旨集(Web)　131st-30th　2019

  7. CD4陽性T細胞のIL-27受容体シグナルにおけるTRAF5の抑制性機能の解明

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    日本薬学会北陸支部例会/日本病院薬剤師会北陸ブロック学術大会プログラム集&要旨集(Web)　131st-30th　2019

  8. Regulation of interleukin-6 receptor signaling by TNF receptor-associated factor 2 and 5 during differentiation of inflammatory CD4+ T cells. Invited Peer-reviewed

    Nagashima H, Ishii N, So T

    Front Immunol　9　1986　2018/08

  9. 東北大学医学部における留年者の原因とアウトカム 過去35年間の卒業生へのアンケート結果

    亀岡 淳一, 石井 直人, 内海 衣恵, 石井 誠一, 大野 勲, 加賀谷 豊

    医学教育　49　(Suppl.)　126-126　2018/07

    Publisher: (一社)日本医学教育学会

    ISSN： 0386-9644

  10. 臨床実習ローテート科と卒業後進路の関係 過去35年間の東北大学卒業生へのアンケートより

    亀岡 浩一, 岩崎 淳也, 内海 衣恵, 石井 直人, 石井 誠一, 加賀谷 豊

    医学教育　48　(Suppl.)　105-105　2017/08

    Publisher: (一社)日本医学教育学会

    ISSN： 0386-9644

  11. LOCAL CONVECTION-ENHANCED DELIVERY OF AN ANTI-CD40 AGONISTIC MONOCLONAL ANTIBODY INDUCES ANTITUMOR EFFECTS

    Takuhiro Shoji, Ryuta Saito, Masashi Chonan, Ichiyo Shibahara, Aya Sato, Masayuki Kanamori, Yukihiko Sonoda, Tooru Kondo, Naoto Ishii, Teiji Tominaga

    NEURO-ONCOLOGY　18　92-92　2016/11

    ISSN： 1522-8517

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  12. CD40 SIGNALING DECREASES MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE (MELK) EXPRESSION AND CORRELATES WITH SURVIVAL IN GLIOBLASTOMA PATIENTS

    Masashi Chonan, Ryuta Saito, Takuhiro Shoji, Ichiyo Shibahara, Masayuki Kanamori, Yukihiko Sonoda, Mika Watanabe, Naoto Ishii, Teiji Tominaga

    NEURO-ONCOLOGY　18　87-88　2016/11

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  13. The Redox function of apurinic/apyrimidinic endonuclease1/redox factor-1 (Ape1/Ref-1) modulates helper T cell response through antigen presenting cells

    N. Akhter, Y. Takeda, H. Nara, A. Araki, N. Asao, N. Ishii, H. Asao

    EUROPEAN JOURNAL OF IMMUNOLOGY　46　972-973　2016/08

    ISSN： 0014-2980

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  14. CD4(+) T cell-intrinsic TRAF5 negatively regulates Th17 cell-dependent experimental autoimmune encephalomyelitis

    H. Nagashima, Y. Okuyama, T. Hayashi, A. Asao, T. Kawabe, S. Yamaki, H. Nakano, M. Croft, N. Ishii, T. So

    EUROPEAN JOURNAL OF IMMUNOLOGY　46　869-869　2016/08

    ISSN： 0014-2980

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  15. TRAF adaptors limit IL-6 receptor signaling through an unexpected binding to the signaling transducer receptor gp130

    T. So, H. Nagashima, Y. Okuyama, T. Hayahi, A. Asao, T. Kawabe, S. Yamaki, H. Nakano, M. Croft, N. Ishii

    EUROPEAN JOURNAL OF IMMUNOLOGY　46　23-24　2016/08

    ISSN： 0014-2980

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  16. シグナル伝達を理解するために必要な知識 第48回 TRAF5を介したシグナル伝達

    宗孝紀, 石井直人

    分子消化器病　12　(4)　399-403　2015/12/01

    ISSN： 1348-995X

  17. EXPANSION OF DYSFUNCTIONAL TIM-3 EXPRESSING EFFECTOR MEMORY CD8+T CELLS DURING SIV INFECTION IN RM

    Tsuyoshi Fujita, Benjamin Burwitz, Glen Chew, Jason Reed, Reesab Pathak, Elizabeth Seger, Kiera Clayton, James Rini, Mario Ostrowski, Naoto Ishii, Marcelo Kuroda, Scott Hansen, Jonah Sacha, Lishomwa Ndhlovu

    JOURNAL OF MEDICAL PRIMATOLOGY　44　(5)　327-327　2015/10

    ISSN： 0047-2565

    eISSN： 1600-0684

  18. 肝外胆管癌におけるNotch signalの関与と治療標的としての可能性

    青木 修一, 水間 正道, 高橋 弥生, 土師 陽一, 岡田 良, 阿部 友哉, 唐澤 秀明, 林 洋毅, 元井 冬彦, 片寄 友, 玉井 恵一, 石井 直人, 海野 倫明

    日本癌学会総会記事　74回　J-1214　2015/10

    Publisher: 日本癌学会

    ISSN： 0546-0476

  19. Investigating the role of the immune checkpoint receptor TIGIT in T cells during HIV disease progression and as a target for immune restoration

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    JOURNAL OF THE INTERNATIONAL AIDS SOCIETY　18　2015/07

    DOI： 10.7448/IAS.18.5.20542 　

    ISSN： 1758-2652

  20. TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4(+) T-Lymphocytes Peer-reviewed

    Takanori So, Hiroyuki Nagashima, Naoto Ishii

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　236　(2)　139-154　2015/06

    DOI： 10.1620/tjem.236.139 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  21. TRAF5を介したシグナル伝達

    宗孝紀, 石井直人

    分子消化器病,先端医学社　12　(4)　83-87　2015

  22. Notch signaling is related to extrahepatic cholangiocarcinoma and a potential therapeutic target

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    日本癌学会学術総会抄録集(Web)　74th　J‐1214 (WEB ONLY)　2015

  23. 免疫応答のチェックポイント ヘルパーT細胞分化におけるTRAF5を介したチェックポイント制御

    宗孝紀, 石井直人

    炎症と免疫　23　(1)　21-26　2014/12/20

    Publisher: (株)先端医学社

    ISSN： 0918-8371

  24. Activation of Notch1 promotes development of human CD8(+) single positive T cells in humanized mice (vol 447, pg 346, 2014)

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    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　452　(1)　206-207　2014/09

    DOI： 10.1016/j.bbrc.2014.08.099 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  25. エフェクター記憶CD4陽性T細胞の恒常性維持増殖におけるOX40およびIL‐7の役割

    山木聡史, 井根省二, 河部剛史, 宗孝紀, 工藤博典, 仁尾正記, 石井直人

    日本小児外科学会雑誌　50　(3)　695-695　2014/04/25

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    ISSN： 0288-609X

  26. エフェクター記憶CD4陽性T細胞の恒常性維持増殖におけるOX40およびIL‐7の役割

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  27. Foamy virus vectorを用いたX連鎖重症複合免疫不全症に対する遺伝子治療モデルの作成

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    ISSN： 0001-6543

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    Publisher: 日本癌学会

    ISSN： 0546-0476

  29. T細胞のメモリー・エフェクターへの分化と関与分子 OX40とIL‐7によるメモリーCD4+T細胞の維持機構

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    月刊臨床免疫・アレルギー科　59　(5)　559-566　2013/05/25

    ISSN： 1881-1930

  30. Rapid Galectin-9 release occurs following HIV-1 acquisition in acute HIV-1 infection

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    JOURNAL OF IMMUNOLOGY　190　2013/05

    ISSN： 0022-1767

  31. OX40(CD134)-OX40リガンド標的. Invited

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    炎症と免疫.　21　(3)　208-212　2013/05

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  33. PS-385-4 蛍光NOGマウスの異種移植モデルを用いた高純度癌細胞サンプリングシステム(PS ポスターセッション,第113回日本外科学会定期学術集会)

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    日本外科学会雑誌　114　(2)　2013/03/05

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    日本小児外科学会雑誌　48　(3)　551-551　2012/05

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    DOI： 10.11164/jjsps.48.3_551_2 　

    ISSN： 0288-609X

  35. B細胞分化と維持の制御プログラム Y染色体連鎖遺伝を示すB細胞欠損症の解析(Y chromosome-linked B cell deficiency in mice)

    Sun Shulan, 河部 剛史, 宗 孝紀, 高橋 武司, 石井 直人

    日本免疫学会総会・学術集会記録　40　142-142　2011/11

    Publisher: (NPO)日本免疫学会

    ISSN： 0919-1984

  36. 第1章 T細胞免疫記憶の総合的理解 2.エフェクター記憶CD4T細胞の生成・維持に及ぼすOX40補助刺激シグナルの役割

    宗孝紀, 石井直人

    実験医学　29　(17)　2755-2759　2011/11/01

    ISSN： 0288-5514

  37. 全ゲノム関連解析による最初のもやもや病遺伝子 RNF213の同定

    鎌田 文顕, 青木 洋子, 成澤 あゆみ, 阿部 裕, 小松崎 匠子, 菅野 潤子, 新堀 哲也, 松原 洋一, 呉 繁夫, 菊池 敦生, 土屋 滋, 藤村 幹, 冨永 悌二, 小野 栄夫, 石井 直人, 大和田 祐二, 真下 陽一, 鈴木 洋一, 羽田 明

    日本小児科学会雑誌　115　(9)　1478-1478　2011/09

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  38. FACS-microarray study of immune cells from patients with schizophrenia

    Chiaki Ono, Zhiqian Yu, Yoichiro Tanabe, Naoto Ishii, Hiroaki Tomita

    NEUROSCIENCE RESEARCH　71　E366-E366　2011

    DOI： 10.1016/j.neures.2011.07.1604 　

    ISSN： 0168-0102

  39. エフェクター記憶CD4T細胞の生成・維持に及ぼすOX40補助刺激シグナルの役割

    宗孝紀, 石井直人

    実験医学,羊土社　29　(17)　29-33　2011

  40. 臓器特異的自己免疫疾患の発症におけるOX40シグナルの関与. Invited

    河部剛史, 石井直人

    炎症と免疫.　18　(6)　628-636　2010/11

  41. OX40-OX40 Ligand Interaction in T-Cell-Mediated Immunity and Immunopathology

    Naoto Ishii, Takeshi Takahashi, Pejman Soroosh, Kazuo Sugamura

    ADVANCES IN IMMUNOLOGY, VOL 105　105　63-98　2010

    DOI： 10.1016/S0065-2776(10)05003-0 　

    ISSN： 0065-2776

  42. Genetic Deletion of OX40 Ligand Suppresses the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice

    Makoto Nakano, Yoshihiro Fukumoto, Kimio Satoh, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    CIRCULATION　120　(18)　S1064-S1064　2009/11

    ISSN： 0009-7322

  43. 肝細胞癌におけるEpCAM陽性細胞のTumor initiating cellの可能性(EpCAM, a possible marker of tumor initiating cell in hepatocellular carcinoma)

    木村 修, 高橋 武司, 石井 直人, 上野 義之, 下瀬川 徹, 菅村 和夫

    日本癌学会総会記事　68回　273-273　2009/08

    Publisher: 日本癌学会

    ISSN： 0546-0476

  44. Differential Roles of Bone Marrow-Derived Progenitor Cells in the Pathogenesis of Vascular Diseases

    Makoto Nakano, Yoshihiro Fukumoto, Kimio Satoh, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　29　(7)　E52-E52　2009/07

    ISSN： 1079-5642

  45. GENETIC DELETION OF OX40 LIGAND SUPPRESSES THE DEVELOPMENT OF ATHEROSCLEROSIS IN APOLIPOPROTEIN E-DEFICIENT MICE

    M. Nakano, Y. Fukumoto, K. Satoh, N. Ishii, K. Sugamura, H. Shimokawa

    ATHEROSCLEROSIS SUPPLEMENTS　10　(2)　2009/06

    ISSN： 1567-5688

  46. GENETIC DELETION OF OX40 LIGAND SUPPRESSES THE DEVELOPMENT OF ATHEROSCLEROSIS IN APOLIPOPROTEIN E-DEFICIENT MICE

    Makoto Nakano, Yoshihiro Fukumoto, Kimio Satoh, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    JOURNAL OF VASCULAR RESEARCH　46　100-100　2009

    ISSN： 1018-1172

  47. 粥状動脈硬化病変における血管新生の抑制をターゲットとした、OX40/OX40L系を介する動脈硬化治療戦略 (血管)

    中野誠, 福本義弘, 佐藤公雄, 伊藤愛剛, 加賀谷豊, 石井直人, 菅村和夫, 下川宏明

    血管　32　(1)　22-22　2009/01

    Publisher: 日本心脈管作動物質学会

    ISSN： 0911-4637

  48. Differential roles for OX40 and IL-7 on homeostasis of effector memory CD4(+) T cells

    Naoto Ishii, Shouji Ine, Pejman Soroosh, Seyed Fazlollah Mousavi, Kazuo Sugamura

    FASEB JOURNAL　22　2008/04

    ISSN： 0892-6638

  49. OX40 Signals Determine the Fate of Memory CD8+T cells following Listeria monocytogenes Infection

    Seyed Fazlollah Mousavi, Pejman Soroosh, Yasunobu Yoshikai, Hao Shen, Kazuo Sugamura, Naoto Ishii

    FASEB JOURNAL　22　2008/04

    ISSN： 0892-6638

  50. Glucocorticoid-induced TNF receptor signals inhibit activation of CD1d-dependent natural killer T cells

    Shuming Chen, Kazuo Sugamura, Naoto Ishii

    FASEB JOURNAL　22　2008/04

    ISSN： 0892-6638

  51. Inhibition of OX40 ligand suppresses the development of atherosclerosis in apolipoprotein E-deficient mice

    Makoto Nakano, Kimio Satoh, Yoshilum Fukumoto, Yoshitaka Ito, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    CIRCULATION　116　(16)　1-2　2007/10

    ISSN： 0009-7322

  52. Co-inhibitory roles for glucocorticoid-induced TNF receptor (GITR) in CD1d-dependent natural killer T cells

    Shuming Chen, Lishomwa C. Ndhlovu, Takeshi Takahashi, Kazuyoshi Takeda, Yoshinori Ikarashi, Pier Paolo Pandolfi, Carlo Riccardi, Masao Ono, Kazuo Sugamura, Naoto Ishii

    CYTOKINE　39　(1)　6-6　2007/07

    DOI： 10.1016/j.cyto.2007.07.026 　

    ISSN： 1043-4666

  53. OX40-OX40L系の自己免疫、アレルギー・炎症性疾患への関与 (分子リウマチ)

    石井直人

    分子リウマチ　4　300-306　2007/07

  54. Important role of erythropoietin receptor in promoting vascular endothelial growth factor expression and angiogenesis in peripheral ischemia in mice

    Makoto Nakano, Kimio Satoh, Yoshihiro Fulkumoto, Yoshitaka Ito, Yutaka Kagaya, Naoto Ishii, Kazuo Sugamura, Hiroaki Shimokawa

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY　27　(6)　E101-E101　2007/06

    ISSN： 1079-5642

  55. 虚血後血管新生に対するErythropoietin/Erythropoietin Receptor Systemの重要性 Erythropoietin Receptor-/- rescued miceによる検討 1 (血管)

    中野誠, 佐藤公雄, 福本義弘, 伊藤愛剛, 加賀谷豊, 石井直人, 菅村和夫, 下川宏明

    血管　30　(2)　55-60　2007/06

    Publisher: 日本心脈管作動物質学会

    ISSN： 0911-4637

  56. 虚血後血管新生に対するErythropoietin/Erythropoietin Receptor Systemの重要性 Erythropoietin Receptor-/- rescued miceによる検討 2 (東北医学雑誌)

    中野誠, 佐藤公雄, 福本義弘, 伊藤愛剛, 加賀谷豊, 石井直人, 菅村和夫, 下川宏明

    東北医学雑誌　119　(1)　92-94　2007/06

  57. 炎症性腸疾患と免疫シグナル (遺伝子医学MOOK)

    石井直人

    遺伝子医学MOOK　6　212-217　2007/06

  58. Important Role of Erythropoietin Receptor to Promote VEGF Expression and Angiogenesis in Peripheral Ischemia in Mice

    NAKANO Makoto, SATOH Kimio, FUKUMOTO Yoshihiro, ITO Yoshitaka, KAGAYA Yutaka, ISHII Naoto, SUGAMURA Kazuo, SHIMOKAWA Hiroaki

    30　(2)　55-60　2007/04/30

    ISSN： 0911-4637

  59. Spontaneous pulmonary hypertension in mice associated with OX40 ligand overexpression

    Moloud Rabieyousefi, Ming-Cai Zhang, Pejman Soroosh, Naoto Ishii, Kazuo Sugamura, Masao Ono

    JOURNAL OF IMMUNOLOGY　178　2007/04

    ISSN： 0022-1767

    eISSN： 1550-6606

  60. OX40 signals preferentially mediate the generation of effector memory but not central memory CD4+T cells

    Pejman Soroosh, Shouji Ine, Kazuo Sugamura, Naoto Ishii

    JOURNAL OF IMMUNOLOGY　178　2007/04

    ISSN： 0022-1767

    eISSN： 1550-6606

  61. STAM1/2ノックアウトマウスは免疫反応を増強する

    井草龍太郎, 村田和子, 田中伸幸, 石井直人, 貫和敏博, 菅村和夫

    日本免疫学会総会・学術集会記録　37　225-225　2007

  62. Application of HSVtk suicide gene to X-SCID gene therapy: Ganciclovir treatment selectively eliminates gene corrected cells in vitro and in vivo

    Toru Uchiyama, Yoshinori Ishikawa, Naoto Ishii, Masafumi Onodera, Miki Sato, Yoji Sasahara, Nobuyuki Tanaka, Kazuo Sugamura, Satoru Kumaki, Shigeru Tsuchiya

    JOURNAL OF GENE MEDICINE　8　(12)　1446-1447　2006/12

    ISSN： 1099-498X

  63. 補助シグナル分子ＯＸ４０と免疫疾患 (Medical Science Digest)

    石井直人

    Medical Science Digest　32　(12)　525-529　2006/10

  64. Regulatory T cells play a very important role for maintenance of allogeneic pregnancy

    Yasushi Sasaki, Akitoshi Nakashima, Satomi Wakasugi, Subaru Myojo, Masatoshi Sakai, Naoto Ishii, Kazuo Sugamura, Shigeru Saito

    PLACENTA　27　(9-10)　A18-A18　2006/09

    ISSN： 0143-4004

  65. Application of HSVtk Suicide Gene to X-SCID Gene Therapy: Ganciclovir Treatment Selectively Elmiinates Gene Corrected Cells In Vitro and In Vivo

    Toru Uchiyama, Yoshinori Ishikawa, Naoto Ishii, Masafumi Onodera, Miki Sato, Yoji Sasahara, Nobuyuki Tanaka, Kazuo Sugamura, Satoru Kumaki, Shigeru Tsuchiya

    MOLECULAR THERAPY　13　S254-S254　2006/05

    ISSN： 1525-0016

    eISSN： 1525-0024

  66. Ｔｈ２優位免疫応答誘導におけるＯＸ４０リガンドの役割 (炎症と免疫)

    石井直人, 菅村和夫

    炎症と免疫　14　(3)　397-402　2006/04

  67. OX40-OX40リガンド系による免疫制御 (感染・炎症・免疫)

    石井直人, 菅村和夫

    感染・炎症・免疫　35　128-141　2005/09

  68. OX40シグナルによるT細胞免疫制御 (炎症と免疫)

    石井直人

    炎症と免疫　13　(6)　683-690　2005/06

  69. OX40-OX40リガンドを標的とした免疫療法 (炎症と免疫)

    石井直人

    炎症と免疫　13　(5)　99-108　2005/05

  70. 新たな免疫分子OX40リガンドによる免疫制御機構の解明 (東北医学雑誌)

    石井直人

    東北医学雑誌　116　42-46　2004/07

  71. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40

    K Sugamura, N Ishii, AD Weinberg

    NATURE REVIEWS IMMUNOLOGY　4　(6)　420-431　2004/06

    DOI： 10.1038/nri1371 　

    ISSN： 1474-1733

  72. T細胞免疫不全症に関与する受容体と細胞内機能因子 (小児内科)

    石井直人

    小児内科　36　1713-1717　2004/01

  73. Expanding role of T-Cell costimulators in regulatory T-Cell function: Recent advances in accessory molecules expressed on both regulatory and nonregulatory T cells

    LC Ndhlovu, Takeda, I, K Sugamura, N Ishii

    CRITICAL REVIEWS IN IMMUNOLOGY　24　(4)　251-266　2004

    DOI： 10.1615/CritRevImmunol.v24.i4.30 　

    ISSN： 1040-8401

  74. 多発性硬化症患者におけるibudilast投与による免疫調整作用の解析

    馮 娟, 三須 建郎, 藤原 一男, 佐古田 三郎, 中辻 裕司, 深浦 彦彰, 菊地 誠志, 田代 邦雄, 錫村 明生, 石井 直人, 菅村 和夫, 中島 一郎, 糸山 泰人

    臨床神経学　43　(12)　1030-1030　2003/12

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

    eISSN： 1882-0654

  75. OX40-OX40 ligand interactions abrogate the suppressive function of CD4(+)CD25(+) regulatory T cells

    Takeda, I, K Murata, LC Ndhlovu, S Satomi, K Sugamura, N Ishii

    FASEB JOURNAL　17　(7)　C216-C216　2003/04

    ISSN： 0892-6638

  76. Sustained OX40-OX40 ligand interactions specifically provoke a biased Th2 response

    N Ishii, A Ndhlovu, K Murata, T Sato, K Sugamura

    FASEB JOURNAL　17　(7)　C227-C227　2003/04

    ISSN： 0892-6638

  77. OX40-OX40リガンド系と自己免疫 (免疫病と感染症)

    石井 直人, 村田 和子, 菅村 和夫

    免疫　2003　202-211　2003

    Publisher: 中山書店

    ISSN： 0918-6557

  78. 胚中心形成におけるB7RP-1/ICOSの役割の解明

    秋葉 久弥, 小潟 英子, 竹田 和由, 村田 和子, 石井 直人, 菅村 和夫, 八木田 秀雄, 奥村 康

    日本免疫学会総会・学術集会記録　32　151-151　2002/10

    ISSN： 0919-1984

  79. Critical role of the OX40/OX40L system in cutaneous immune responses

    T Sato, N Ishii, K Murata, LC Ndhlovu, K Kikuchi, K Sugamura

    FASEB JOURNAL　16　(4)　A717-A717　2002/03

    ISSN： 0892-6638

  80. OX40L-transgenic mice develop autoimmune diseases linked to failed induction of peripheral T cell tolerance

    K Murata, N Ishii, M Nose, M Yamada, LC Ndhlovu, K Sugamura

    FASEB JOURNAL　16　(5)　A1064-A1064　2002/03

    ISSN： 0892-6638

  81. 抗IL-21受容体単クロン抗体を用いたIL-21受容体の解析

    浅尾裕信, 石井直人, 多田孝太郎, 久間木悟, 土屋滋, 菅村和夫

    日本免疫学会総会・学術集会記録　32　170-170　2002

  82. STAM1/2ダブルノックアウトマウスにおけるT細胞分化・成熟障害

    山田 充啓, 浅尾 裕信, 石井 直人, 村田 和子, 佐々木 義輝, 竹下 敏一, 菅村 和夫

    日本免疫学会総会・学術集会記録　31　181-181　2001/12

    Publisher: (NPO)日本免疫学会

    ISSN： 0919-1984

  83. OX40/OX40リガンドによる免疫調節 (アレルギー科)

    石井直人

    アレルギー科　11　260-267　2001/09

  84. 抗原提示細胞上のOX40リガンド（OX40L）の役割 (実験医学)

    石井直人, 菅村和夫

    実験医学　19　596-601　2001/06

  85. OX40 ligand signals are critical for the T-cell priming events during experimental autoimmune encephalomyelitis

    LC Ndhlovu, N Ishii, K Morata, T Sato, K Sugamura

    FASEB JOURNAL　15　(4)　A344-A344　2001/03

    ISSN： 0892-6638

  86. 抗原提示機能にかかわる新たな分子OX40リガンド (免疫調節の分子機構)

    石井 直人, 村田 和子, 菅村 和夫

    免疫　2000　172-182　2001

    Publisher: 中山書店

    ISSN： 0918-6557

  87. 多発筋炎および肉芽腫性筋炎における OX40 発現の免疫組織学的検討

    竪山 真規, 藤原 一男, 石井 直人, 菅村 和夫, 小野寺 好明, 糸山 泰人

    Neuropathology : official journal the Japanese Society of Neuropathology　20　78-78　2000/06/01

    ISSN： 0919-6544

  88. 免疫不全症候群の原因遺伝子 (遺伝子医学)

    石井直人, 菅村和夫

    遺伝子医学　3　22-26　1999/05

  89. (9)重症筋無力症胸腺におけるIL-2受容体発現の検討(第18回日本胸腺研究会)

    永田 哲也, 小野寺 宏, 藤原 一男, 鈴木 靖士, 糸山 泰人, 石井 直人, 菅村 和夫, 大内 将弘, 井口 篤志, 田林 洸一, 半田 政志

    日本呼吸器外科学会雑誌　13　(2)　1999/03/15

    Publisher: 特定非営利活動法人日本呼吸器外科学会

    ISSN： 0919-0945

  90. 重症筋無力症及び正常胸腺単核細胞の3カラー表面マーカー解析

    永田 哲也, 藤原 一男, 小野寺 宏, 小野寺 淳一, 糸山 泰人, 石井 直人, 菅村 和夫, 大内 将弘, 庄司 好己, 田林 晄一

    臨床神経学　39　(1)　136-136　1999/01

    Publisher: (一社)日本神経学会

    ISSN： 0009-918X

  91. 重症筋無力症胸腺におけるapoptosis関連分子の発現

    小野寺宏, 永田哲也, 藤原一男, 鈴木靖士, 糸山泰人, 石井直人, 菅村和夫

    日本免疫学会総会・学術集会記録　28　136　1998/10

    ISSN： 0919-1984

  92. 重症筋無力症胸腺におけるIL‐2受容体

    永田哲也, 小野寺宏, 藤原一男, 糸山泰人, 石井直人, 菅村和夫

    日本免疫学会総会・学術集会記録　28　156　1998/10

    ISSN： 0919-1984

  93. 重症筋無力症胸腺におけるapoptosis関連分子の発現

    小野寺 宏, 永田 哲也, 藤原 一男, 鈴木 靖士, 糸山 泰人, 石井 直人, 菅村 和夫

    日本臨床免疫学会会誌　(26回抄録集)　136-136　1998/10

    Publisher: 日本臨床免疫学会

    ISSN： 0911-4300

  94. 重症筋無力症胸腺におけるIL-2受容体

    永田 哲也, 小野寺 宏, 藤原 一男, 糸山 泰人, 石井 直人, 菅村 和夫

    日本臨床免疫学会会誌　(26回抄録集)　156-156　1998/10

    Publisher: 日本臨床免疫学会

    ISSN： 0911-4300

  95. Ｘ連鎖重症複合免疫不全症（XSCID）・サイトカイン共通γ鎖 (現代医療)

    石井直人, 菅村和夫

    現代医療　30　274-277　1998/10

  96. サイトカイン共通受容体γ鎖とＸ連鎖重症複合免疫不全症 (小児内科)

    石井直人

    小児内科　30　51-56　1998/07

  97. Immunopathological role of IL-7 in the development of X-linked severe combined immunodeficiency (X-SCID)

    S Kumaki, N Ishii, M Minegishi, S Tsuchiya, D Cosman, K Sugamura, T Konno

    FASEB JOURNAL　12　(5)　A920-A920　1998/03

    ISSN： 0892-6638

  98. Analysis of surface marker of severe myasthenia and normal thymus gland monocyte (3-color flow cytometric analysis). (Ministry of Health and Welfare S).

    永田哲也, 藤原一男, 小野寺淳一, 石井直人, 菅村和夫, 大内将弘, 庄司好己, 田林晃一, 糸山泰人

    免疫性神経疾患調査研究分科会 平成9年度研究報告書　47-49　1998

  99. 免疫性神経疾患におけるOX40/gp34

    藤原一男, 小野寺淳一, 永田哲也, 竪山真規, 東村紀一, 石井直人, 菅村和夫, 大内将弘, 糸山泰人

    Neuroimmunol　6　(1)　16　1998/01

    ISSN： 0918-936X

  100. 重症筋無力症胸腺におけるT‐cellと細胞死関連分子

    小野寺宏, 永田哲也, 藤原一男, 小野寺淳一, 糸山泰人, 石井直人, 菅村和夫

    Neuroimmunol　6　(1)　23　1998/01

    ISSN： 0918-936X

  101. Ｘ連鎖重症複合免疫不全症（XSCID） (医学のあゆみ)

    石井直人

    医学のあゆみ　182　717-721　1997/09

  102. Ｔ細胞系のシグナル伝達 (小児内科)

    石井直人

    小児内科　29　811-816　1997/08

  103. 重症複合免疫不全症、小児疾患診療のための病態生理 (小児内科)

    石井直人

    小児内科　29　988-994　1997/08

  104. サイトカインシグナル伝達と免疫不全 (最新医学)

    石井直人, 菅村和夫

    最新医学　52　824-829　1997/07

  105. IL-2受容体γ鎖と免疫不全 (病理と臨床)

    石井直人, 菅村和夫

    病理と臨床　15　70　1997/04

  106. Expression of OX40/gp34 in the myasthenic thymus.

    小野寺淳一, 永田哲也, 藤原一男, 糸山泰人, 石井直人, 菅村和夫, 大内将弘

    免疫性神経疾患調査研究分科会 平成8年度研究報告書　89-91　1997

  107. サイトカイン共通γ鎖（γc鎖）とＸ連鎖重症複合免疫不全症（XSCID） (日常診療と血液)

    石井直人

    日常診療と血液　7　35-40　1997/01

  108. Expression of the common gamma chain on fetal thymocytes in human

    N Ishii, N Yaegashi, K Sugamura

    TISSUE ANTIGENS　48　(4-II)　CR101-CR101　1996/10

    ISSN： 0001-2815

    eISSN： 1399-0039

  109. The interleukin-2 receptor gamma chain: Its role in the multiple cytokine receptor complexes and T cell development in XSCID

    K Sugamura, H Asao, M Kondo, N Tanaka, N Ishii, K Ohbo, M Nakamura, T Takeshita

    ANNUAL REVIEW OF IMMUNOLOGY　14　179-205　1996

    DOI： 10.1146/annurev.immunol.14.1.179 　

    ISSN： 0732-0582

  110. サイトカイン共通レセプターγc鎖の機能とその異常 (Molecular Medicine)

    石井直人, 菅村和夫

    Molecular Medicine　32　1268-1275　1995/12

  111. THE COMMON GAMMA-CHAIN FOR MULTIPLE CYTOKINE RECEPTORS

    K SUGAMURA, H ASAO, M KONDO, N TANAKA, N ISHII, M NAKAMURA, T TAKESHITA

    ADVANCES IN IMMUNOLOGY, VOL 59　59　225-277　1995

    ISSN： 0065-2776

  112. THE COMMON GAMMA-CHAIN FOR MULTIPLE CYTOKINE RECEPTORS Peer-reviewed

    K SUGAMURA, H ASAO, M KONDO, N TANAKA, N ISHII, M NAKAMURA, T TAKESHITA

    ADVANCES IN IMMUNOLOGY, VOL 59　59　225-277　1995

    ISSN： 0065-2776

  113. IL-2受容体γ鎖の機能異常と伴性重症複合免疫不全症（XSCID） (小児科診療)

    石井直人, 菅村和夫

    小児科診療　57　1072-1077　1994/11

  114. RECONSTITUTION OF THE FUNCTIONAL IL-2 RECEPTOR COMPLEX - INVOLVEMENT OF THE IL-2 RECEPTOR GAMMA-CHAIN IN SIGNAL-TRANSDUCTION

    H ASAO, T TAKESHITA, N ISHII, M NAKAMURA, K SUGAMURA

    JOURNAL OF CELLULAR BIOCHEMISTRY　395-395　1994

    ISSN： 0730-2312

  115. STRUCTURE AND FUNCTION OF THE HETEROTRIMER SUBUNIT COMPLEX OF IL-2 RECEPTOR

    M KONDO, T TAKESHITA, N ISHII, M NAKAMURA, S WATANABE, K ARAI, K SUGAMURA

    JOURNAL OF CELLULAR BIOCHEMISTRY　403-403　1994

    ISSN： 0730-2312

  116. 原発性免疫不全症の新しい展開 伴性重症複合免疫不全症とIL-2レセプターγ鎖遺伝子 (炎症と免疫)

    土屋滋, 石井直人

    炎症と免疫　2　(5)　484-491　1994

  117. Commonγ鎖の機能とその異常：伴性重症複合免疫不全症（XSCID） (炎症と免疫)

    石井直人, 菅村和夫

    炎症と免疫　2　70-76　1994/01

  118. IL-2受容体γ鎖の機能異常と伴性重症複合免疫不全症 (実験医学)

    石井直人, 菅村和夫

    実験医学　12　31-35　1994/01

  119. インターロイキン２（IL-2） (Medical Technology)

    石井直人, 菅村和夫

    Medical Technology　21　632-635　1993/07

  120. IL-2受容体のγ鎖の機能とXSCID (免疫・Immunology Frontier)

    石井直人, 菅村和夫

    免疫・Immunology Frontier　3　351-354　1993/05

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Books and Other Publications 21

  1. サイトカイン・増殖因子 用語ライブラリー

    菅村和夫ほか, d, 石井直人

    羊土社　2005/03

  2. サイトカイン・増殖因子

    菅村和夫ほか, d, 石井直人

    羊土社　2005/03

  3. サイトカイン・増殖因子、用語ライブラリー

    菅村和夫, 宮園浩平ほか, d, 石井直人

    羊土社　2005/03

  4. サイトカイン・増殖因子 用語ライブラリー

    菅村和夫ほか, d, 石井直人

    羊土社　2005/03

  5. 免疫2003

    岸本忠三, d, 石井直人, 村田和子, 菅村和夫

    中山書店　2003/10

  6. Annual Review 血液2002

    高久史麿, 石井直人

    中外医学社　2002/06

  7. 生体防御 免疫と感染症

    谷口克, 谷口維紹, 石井直人, 菅村和夫

    共立出版　2001/01/30

  8. 新女性医学大系

    武谷雄二, 石井直人

    中山書店　2000/10

  9. Bio Science用語ライブラリー

    宮園浩平, 石井直人

    羊土社　1998/11

  10. 用語ライブラリー サイトカイン・増殖因子 改訂版

    宮園浩平, 石井直人

    羊土社　1998/11

  11. 血液疾患 state of arts (Ver. 2)、別冊・医学のあゆみ

    溝口秀昭, 平井久丸, 坂田洋一, 石井直人

    医歯薬出版　1998/07

  12. サイトカイン実験法

    宮島篤, 山本雅 ed, 石井直人, 竹下敏一, 菅村和夫

    羊土社　1997/06

  13. Bio Science用語ライブラリー 遺伝子病

    中村祐輔, 石井直人, 菅村和夫

    羊土社　1996/11

  14. 免疫疾患の最新到達点

    高久史麿, 石井直人, 菅村和夫

    メディカルレビュー社　1996/08

  15. 遺伝子病マニュアル（下）

    垂井清一郎, 多田啓也, 石井直人

    中山書店　1996/04

  16. Bio Science用語ライブラリー、サイトカイン・増殖因子

    宮園浩平, 菅村和夫, 石井直人

    羊土社　1995/11

  17. Bio Science用語ライブラリー サイトカイン・増殖因子

    宮園浩平, 菅村和夫, 石井直人

    羊土社　1995/11

  18. Bio Science用語ライブラリー サイトカイン・増殖因子

    宮園浩平, 菅村和夫, 石井直人

    羊土社　1995/11

  19. Annual Review 免疫 1995

    菊地浩吉ほか, d, 石井直人, 菅村和夫

    中外医学社　1995/10

  20. 免疫疾患ーstate of arts、別冊・医学のあゆみ

    今西二郎ほか, d, 石井直人, 菅村和夫

    医歯薬出版株式会社　1995/08

  21. 別冊・医学のあゆみ、サイトカインー基礎から臨床まで

    今西二郎, 石井直人, 菅村和夫

    医歯薬出版　1992/11

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Research Projects 52

  1. Regulation of T cell immune responses by supersulfide

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  2. Development of a method for activation of costimulatory immune receptors by using their corresponding multimerized ligands

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Research (Exploratory)

    Institution: University of Toyama

    2023/06/30 - 2025/03/31

  3. 新たな自己反応性T細胞の恒常性維持機構ならびに生理的・病理的意義の解明

    河部 剛史, 石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 基盤研究(B)

    Institution: 東北大学

    2022/04/01 - 2025/03/31

  4. Regulation of allergic and autoimmune responses by ILC2-T cell interaction

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2020/04/01 - 2023/03/31

  5. Proof of a novel gene underlying B lymphocyte deficiency using genome-edited mice

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2020/04/01 - 2023/03/31

  6. Characterization of multifunctional roles of TRAF5 in pro-inflammatory cytokine receptor signaling

    SO Takanori

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: University of Toyama

    2018/04/01 - 2021/03/31

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    In this study, we found novel roles of TRAF5 in immunity and inflammation: 1) negative regulatory function of TRAF5 in signaling mediated by receptors for IL-6 and IL-27, 2) significance of TRAF5 in differentiation and effector function of plasmacytoid dendritic cells, 3) inflammatory function of TRAF5 in lung inflammation mediated by OSM, 4) inflammatory function of TRAF5 in colonic inflammation mediated by DSS. These results indicate that TRAF5 expressed by different cell types controls inflammatory signaling in both positive and negative ways. Further study is essential to understand the regulatory roles of TRAF5 and its family molecules in health and diseases.

  7. GITR signaling regulates ILC2 function

    Okuyama Yuko

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2017/04/01 - 2020/03/31

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    Group2 innate lymphoid cells (ILC2) produce large amounts of type 2 effector cytokines such as IL-5 and IL-13 that cause allergy. ILC2 in the lung highly express glucocorticoid-induced TNFR-related protein (GITR), and thus we hypothesized that GITR plays an important role in ILC2. We here show that GITR-deficiency or blockade of GITR signaling in mice displayed attenuated lung inflammation and that GITR signaling in ILC2 was important for type 2 cytokine production. Ligation of both GITR and IL-33-receptor synergistically activated NF-κB, p38, and Erk signals in ILC2, resulting in IL-9 production, leading to STAT5-driven IL-5 and IL-13 production. Moreover, we found murine ILC2 express both GITR and GITR-L, and autocrine interaction affect ILC2 activation.

  8. Transmission dynamics of Respiratory Syncytial Virus and Establishing New Control Measures

    Oshitani Hitoshi, Okamoto Michiko, Saito Mariko, Furuse Yuki, Otomaru Hirono, Ueno Fumihiko, Clyde Dapat, LUPISAN Socorro P., TALLO Veronica, ALDAY Portia P., MERCADO Edelwisa S., Sirjan Bastola, Malasao Rungnapa, Alexander Burmaa, Od Isn

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2016/04/01 - 2019/03/31

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    We conducted a cohort study in the Philippines, which focused on RSV(Respiratory Syncytial Virus) and virological and epidemiological analyses were conducted. We revealed that some amino acid substitutions might be involved for repeated infections with RSV. We also calculated the age-specific incidence of RSV and identified older children as an important source of RSV infection for infants. We also conducted a cohort study in Mongolia and revealed transmission patterns of RSV in the community. In Zambia, we started a preliminary sequence analysis of RSV and identified a unique mutation in analyzed viruses.

  9. Roles for TNFR superfamily molecules in regulation of ILC function

    ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2016/04/01 - 2018/03/31

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    Group 2 innate lymphoid cells (ILC2) in the lung are activated by inhaled allergens and epithelial cytokine interleukin 33 (IL-33). We found that IL-33 alone was not sufficient to induce optimal ILC2 activation and that additional signals from glucocorticoid-induced TNFR-related protein (GITR) were essential. Gitr -/- mice displayed reduced numbers of ILC2 after administration of papain or IL-33, which resulted in impaired expression of IL-5 and IL-13 and diminished eosinophilia in the lung. Crosslinking of GITR with IL-33 synergistically activated NF-κB, p38, and Erk to induce IL-9 production, and autocrine IL-9 promoted IL-5 and IL-13 via STAT5. Accordingly, STAT5 activators, IL-2 and IL-9, restored the defective responses of Gitr -/- ILC2. Our results identify a previously unknown critical role for GITR co-signaling in initiating and promoting early ILC2 activation in the lung.

  10. Mechanism of sublingual immune tolerance induction by cross-talking with gut mucosal immunity

    SUGAWARA Shunji, ISHII Naoto, TANAKA Yukinori, NAGASHIMA Hiroyuki, LU Lu, SHISHIDO Kaori

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

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    Sublingual immunotherapy (SLIT) is an allergen-specific treatment for allergy. SLIT operates by acting on the sublingual mucosa and increases allergen tolerance with safety and effective effect. However, the underlying immunological mechanism remain unclear. This study aimed at providing evidence that sublingual immune tolerance is induced by cross-talking with gut mucosal immunity. This study showed that after sublingual application of antigen, antigen was captured by macrophages, transferred to migratory dendritic cells, and antigen-specific regulatory T cells were induced in the draining (submandibular) lymph modes. This study also showed that Langerhans cells in sublingual mucosa were not responsible for the induction of sublingual immune tolerance, and that sublingual immune tolerance was related to intestinal immune tolerance.

  11. Identification and analysis of the niches for helper memory T cells

    ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

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    Accumulating evidence suggests that mesenteric lymph nodes (MLNs) play important roles in gut-tropic Th17 cell generation, although it is still unclear if MLNs are involved in the pathogenesis of small intestinal inflammation. To address this issue, we analyzed the roles of both MLNs and Peyer’s patches (PPs) by evaluating MLN- or PP-deficient mice in an experimental model of small intestinal inflammation. MLNs, but not PPs, were essential for the pathogenesis of the intestinal inflammation, in particular the accumulation and infiltration of Th17 cells. Furthermore, MLN removal led to a significantly reduced number of peripheral α4β7+ CD4+ effector memory T (TEM) cells under normal conditions, suggesting that MLNs may play a role in maintaining the number of gut-tropic Th17-TEM cells circulating in the blood. Taken together, the present study highlights the important role of MLNs in contributing to the pathogenesis of small intestinal inflammation.

  12. Regulation of inflammatory cytokine signaling by TRAF5

    SO TAKANORI

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    2015/04/01 - 2018/03/31

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    IL-17-producing helper CD4+ T cells, Th17 cells, control not only host defense against pathogens but also immune pathogenesis of inflammatory and autoimmune diseases. Th17 cells differentiate from antigen-primed naive CD4+ T cells in response to IL-6, and the IL-6-receptor signaling plays a dominant role for the development of Th17 cells. In this study, we found that TRAF2 and TRAF5 associated with the signal-transducing receptor gp130 expressed by naive CD4+ T cells differentially regulated the instructive IL-6-receptor signaling that is needed for the development of Th17 cells.

  13. Pouchitis develops due to change of sodium concentration

    Kouhei Fukushima

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2014/04/01 - 2016/03/31

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    A pouch using the small intestine (ileal pouch) is constructed in surgical treatment of ulcerative colitis to preserve the anus. Development of pouchitis, inflammation of the pouch, is the most frequent troublesome after surgery. Its pathogenesis and radical therapeutics still remains unknown. We initially tried to analyze an animal model of this disease but failed. We successively investigated bacterial composition in stool from the pouch. Antibacterial drugs are now most frequently used for the medical treatment of pouchitis. We successfully demonstrated that the ratio of bacteria with genetic mutations, which guarantee resistance to ciprofloxacin, an antibacterial drug, increases after the therapy. This may be the reason why pouchitis is sometimes resistant to the ciprofloxacin therapy, and behaves as a chronic and intractable disease.

  14. Development of novel immunotherapy against malignant glioma

    SAITO RYUTA, ISI Nato, KIKUCHI Toshiaki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2013/04/01 - 2015/03/31

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    In the preceding study, we attempted to develop the new immunotherapeutic strategy using one of the costimulatory molecule, OX40. In the present study, we attempted to augment the efficacy of OX40 stimulation by adding it to subcutaneous tumor vaccination therapy. However, during our effort to augment the efficacy by adding similar costimulation molecule, CD40, we realized that CD40 evokes stronger antitumor effect than OX40. Therefore, we concentrated on CD40 and tried to develop effective immunotherapeutic strategy using this molecule. From analyses of clinical tumor samples, we demonstrated that gene expression of CD40 and CD40L (ligand) corresponded with the patients’ progression-free and overall survival. Subsequently, we demonstrated the efficacy of CD40 stimulation by adding CD40 agonistic antibody to subcutaneous tumor vaccines. This strategy prolonged the survival of intracranial tumor models in both glioma model and glioma initiating cell derived glioma models.

  15. Roles of TRAF5 in the lineage commitment of helper T cell subsets

    SO Takanori, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2012/04/01 - 2015/03/31

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    Helper T-lymphocytes (Th cells) promotes immune-mediated inflammatory diseases, such as allergic asthma and rheumatoid arthritis. Signaling via IL-6 contributes to the development of the Th17 subset, which is one of major subpopulations of Th cells. Th17 cells activate neutrophils and are involved in autoimmune diseases. This study demonstrates that TRAF5 adaptor protein constitutively associates with a cytoplasmic region in the signaling transducing receptor for IL-6, gp130, to inhibit the IL-6 signaling and that TRAF5 works as an anti-inflammatory factor to limit immune responses mediated by pathogenic Th17 cells.

  16. Development of a highly efficient gene targeting strategy using adenovirus-mediated delivery of donor DNA and artificial nucleases

    MITANI Kohnosuke, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Saitama Medical University

    2012/04/01 - 2015/03/31

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    Several strategies are known to enhance gene targeting in mammalian cells. Expression of sequence-specific nucleases, such as TALENs and CRISPRs, introduces DNA double-strand breaks at the target chromosomal sites, thus stimulating homology-mediated DNA repair. As an alternative strategy, delivery of donor DNA by a helper-dependent adenoviral vectors (HDAdV), also reportedly enhances gene targeting efficiencies. In this study, we combined TALEN/CRISPR expression and HDAdV-mediated delivery of donor DNA for gene targeting at the HPRT and the IL2RG loci in human induced pluripotent stem cells. At both loci, the combination of the nucleases and donor HDAdV enhanced the targeting efficiencies by ~2 folds. Delivery of both the nuclease and the donor DNA by a single HDAdV further enhanced the targeting by additional ~2 folds. These results suggest that adenovirus-mediated gene targeting technologies can be further improved in a variety of cells.

  17. Roles of OX40 and IL-7 in homeostasis of memory T cells

    ISHII NAOTO, SO Takanori

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2012/04/01 - 2015/03/31

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    T-cell homeostasis preserves the numbers, the diversity and functional competence of different T cell subsets that are required for adaptive immunity. It is not clear how memory CD4+ T cell subsets are maintained in the periphery and what factors are responsible for the maintenance. To examine the homeostatic mechanisms, CFSE-labeled CD4+ effector memory T (TEM) cells were transferred into syngeneic C57BL/6 mice, and the systemic cell proliferative responses were assessed by CFSE dye dilution. We found that the fast homeostatic proliferation of TEM cells was strictly regulated by both antigen and OX40 costimulatory signals and that the slow proliferation was dependent on IL-7. The OX40-dependent fast proliferation preferentially expanded IL-17-producing helper T cells (Th17 cells). Together, both OX40 and IL-7 signals are required during homeostasis of TEM cells, and the synergistic signals may be critical for the expansion of Th17 cells.

  18. Development of a novel human leukemia model using humanized mice

    ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    In vivo studies in which primary human leukemia cells were transplanted into immunodeficient mice, provided significant advances in our understanding of the pathogenesis of human leukemia. However, these models, in which the leukemia cells had already developed in human patients before being transplanted into mice, are not suitable for studying physiological leukemogenesis. Therefore, we here developed a new experimental model for analyzing leukemogenesis in which primary human HSCs are converted into leukemia cells by deliberate genetic hits. We hope that this newly established model using humanized mice will contribute to future studies aimed at revealing the molecular mechanisms for leukemogenesis and developing new therapies against leukemia.

  19. T-cell costimulation-mediated regulation of mucosal inflammation

    ISHII Naoto, ONO Masao, KINOUCHI Yoshitaka

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2009 - 2011

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    We examined a quantitative trait locus (QTL)that may make C57BL/6 (B6)mice susceptible and BALB/c mice resistant to IBD developing in OX40 ligand-transgenic (OX40L-Tg)mice. The locus exhibits highly significant logarithm of odd (LOD)score for the IBD severi ty. Further positional mapping performed using single nucleotide polymorphisms (SNPs)at this locus revealed the lowest p-value (<10-7 )for the SNP in TNFRSF14 gene. TNFRSF14 encodes the herpes virus entry mediator (HVEM), which belongs to the TNF recepto r superfamily.

  20. Mechanisms and their regulation of autoimmune disorders

    YAMAMOTO Kazuhiko, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: The University of Tokyo

    2007 - 2011

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    We have observed that in the presence of strong proliferation of antigen-X-specific T cells, co-existing T cells specific to antigen-Y exhibit activation in response to small amount of antigen-Y. We termed this phenomenon as 'Extended antigen presentation (EAP)', a new mechanism of naive T cell activation. This project revealed that the induction of EAP depends on cell-cell contact and the amount of EAP-inducing antigen is as small as that of physiological autoantigen. Moreover, the fact that EAP induction was observed in three different T cell receptor transgenic T cells suggested universal nature of this phenomenon. EAP may be an immunological basis for epitope-spreading in autoimmune disease, and our observation could contribute to the understanding of autoimmunity and the development of therapeutic strategy.

  21. Leukemogenesis due to insertional mutagenesis-a NOG mouse model-

    TSUCHIYA Shigeru

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2007 - 2009

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    Humanized NOD/shi-scid/gammac (null) (NOG) mice (hu-HSC NOG mice) model was established in order to know the safety and efficacy of human gene therapy. We found that LMO-2 gene-introduced human cord blood stem cells showed transient proliferation in NOG mice, but did not induce leukemia at all. The conclusion is that the second hit by an additional oncogene must be required to complete the leukemogenic process.

  22. 小胞輸送分子Hrsを介する細胞老化とがん細胞悪性形質の制御

    石井 直人, 田中 伸幸

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    Institution: 東北大学

    2008 - 2008

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    HeLa細胞において, 細胞内小胞輸送関連タンパク質HrsをSiRNAを用いてノックダウンするとβGal活性の上昇などの細胞老化が観察された。そこで, Hrsによる癌細胞老化抑制機序を明らかにするために, Hrs欠損マウス由来細胞をin vitroで癌化することにより, Hrs完全欠損の癌細胞老化における効果を検討することを試みた。最初に, LysM-Cre/Hrs^<flox/flox>マウス由来線維芽細胞(Hrs^<flox/flox>MEF)およびLysM-Creマウス由来線維芽細胞(WT-MEF)にSV40-LargeT遺伝子を導入し不死化細胞を得た。さらにHrs^<flox/flox>MEFおよびWT-MEF細胞に活性化型H-ras遺伝子を導入し癌化した各細胞株も樹立した。これらの細胞の長期培養を行い, βGal活性の上昇、INK4a発現を指標に, 細胞老化の程度を検討した。しかしながら, Hrsの有無により明らかな細胞老化の差異は観察されなかった。また, in vitroの細胞増殖能にも有意な差異を認めなかった。従って, HeLa細胞で見られたHrsノックダウンで見られた効果は残念ながらHrs欠損マウス由来のMEF細胞株では再現できなかった。その原因として, ヒトとマウスにおけるHrsの役割の違いや, 遺伝子ノックダウン法によるHrs不完全欠損と, 遺伝子欠損マウス由来組織におけるHrs完全欠損の細胞おける効果の違いなどが考えられた。以上の実験結果により, 当初の研究計画は途上で断念せざるを得ない結果となった。

  23. 脱ユビキチン化酵素AMSH、AMSH-LPによるタンパク質分解機構の解明

    石井 直人, 田中 伸幸

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2007 - 2008

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    本研究者は以前に、脱ユビキチン化酵素AMSHの遺伝子欠損マウスを作製した。その結果, 同マウスが神経変性疾患を発症することを見出した。さらなる解析により、AMSH欠損マウスの変性神経細胞内にユビキチン化タンパクが蓄積していることが分かった。これらの事実は、脱ユビキチン化酵素AMSHが、基質タンパク質のタンパク分解を制御することにより、神経細胞生存・維持に重要な役割を担っていることを示唆する。また、申請者はAMSHのファミリー分子AMSH-LPを遺伝子単離し、AMSH-LPがAMSHと同等の脱ユビキチン化酵素活性を有することを見いだした。また, AMSH-LPが神経組織に比較的広範囲に発現することを確認した。そこで、AMSH-LP遺伝子欠損マウスを作成し, 神経系の異常について解析を行った。しかし, 1歳齢までの種々の週齢で解析を行ったが, 神経組織に明らかな異常は認められず, またAMSH欠損マウスの観察された神経細胞内にユビキチン化タンパク質の蓄積も認められなかった。また, 2歳齢まで観察を続けたが神経系の異常を疑わせる所見は得られなかった。さらに, AMSHとAMSH-LPの2重欠損マウスを作成したが, AMSHの単独欠損マウスに認められる所見と同程度の神経変性疾患様の症状と組織学的神経変性を認めるのみで, AMSH-LP欠損による疾患増悪効果は観察されなかった。従って, AMSH-LPは神経組織に発現するにも関わらずAMSHのような重要な機能を有しておらず, AMSHとAMSH-LPには機能的相違が存在するものと考えられだ。

  24. 肺高血圧症の分子機構における免疫系細胞活性化分子の役割の解明

    下川 宏明, 石井 直人, 小野 栄夫, 星川 康

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    Institution: 東北大学

    2006 - 2007

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    これまで我々は、OX40Lが抗原提示細胞や血管内皮に発現しており、T細胞と抗原提示細胞のOX40/OX40L系を介する相互作用がT細胞活性化に必須であることを明らかにしてきた。さらに本研究にあたって、低酸素状態(O_210%)で飼育したマウスの肺血管内皮ではOX40Lの発現が亢進し、その周囲にCD4陽性T細胞が集族することを確認しているが、その病理学的意義は不明である。こうした未解決の点を踏まえ、本研究では血管病変進行におけるOX40/OX40L系の意義、特に肺高血圧症の重要な病理学的変化である肺動脈リモデリングとの関連を明らかにする目的で、OX40/OX40L系の肺高血圧症進行における意義に関する検討を行うため、平成19年度に、以下の実験を行った。 <骨髄置換モデルにおける肺高血圧の評価> 前年度に、OX40L遺伝子欠損マウスにおいて肺高血圧症が軽減されることを示したため、その機序を解析するべく、骨髄細胞をGFP-野生型マウス/GFP-OX40L遺伝子欠損マウス、体細胞側を野生型マウス/OX40L遺伝子欠損マウスと振り分けた4種類の骨髄置換キメラマウスを作成し、低酸素性肺高血圧モデルを作成した。結果、骨髄、体細胞のどちらかがOX40L遺伝子欠損マウスのキメラマウスは、骨髄、体細胞ともに野生型のキメラマウスに比し、肺高血圧の程度が軽く、肺組織における骨髄由来の細胞が少ない傾向であった。この傾向は骨髄、体細胞ともにOX40L遺伝子欠損マウスのキメラマウスにおいて更に顕著となった。この結果から、骨髄細胞ならびに肺血管局所のOX40L双方が肺組織への骨髄細胞の動員、低酸素性肺高血圧モデルの進展に関与していることが示唆された。

  25. Regulation of effector T cells that mediate inflammatory responses

    ISHII Naoto, MURATA Kazuko, TAKAHASHI Takeshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2006 - 2007

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    OX40 is a member of TNF receptor superfamily molecules that provide T-cell costimulatory signals. The presence of (OX40^+ lymphocytes and OX40 ligand^+ (OX40L)^+ cells at the sites of inflammation in T cell-mediated immune disorders, such as autoimmunity, allergic and infectious diseases, and GVHD is well documented. These observations suggest important roles for OX40-OX40L interactions in T-cell mediated inflammatory responses. We thus have attempted to elucidate the critical roles for OX40 on the inflammatory responses. In this study, we have founded at least two distinct mechanisms for OX40-mediated T cell inflammation. Concerning the first mechanism, we have demonstrated that OX40 signals preferentially promote the generation of effector memory CD4 T cells, which are mainly involved in organ-specific immune responses containing inflammation, rather than central memory CD4 T cells, which mediate systemic immune responses. This can explain several previous findings that OX40 enhances organ-specific inflammation, but not systemic immune responses. Secondly, we have shown that deliberate OX40 signals suppress in vitro differentiation of inducible regulatory T (iTreg) cells, which can be induced from naive CD4 T cells upon stimulation with antigen in the presence of TGFβ. In contrast, inhibition of OX40 signals during the Treg inducible stimulation promoted iTreg cell generation. These results suggest that excessive OX40 signals may lead to a failed induction of Treg-mediated immune tolerance, and that suppression of OX40 signals may enhance Treg-mediated immune tolerance. To fully understand the OX40 roles on T-cell mediated inflammation, further in vivo studies are required.

  26. T細胞免疫記憶に関する細胞外環境の解析

    菅村 和夫, 石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2006 - 2007

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    【目的】免疫記憶の中心的な役割を担う記憶T細胞は、臓器特異的に存在し局所の免疫反応を司るエフェクター記憶T(T_<EM>)細胞と、超長期に生存し全身性の免疫反応に関与するセントラル記憶T(T_<CM>)細胞とに大別される。両者共にナイーブT細胞から分化することが知られているが、その存在部位が前者は臓器局所、後者はリンパ組織であるなど、その挙動は大きく異なる。従って、T_<EM>細胞とT_<CM>細胞の分化・生存に関わる細胞外環境も両者で大きく異なるものと推察される。本研究では、CD4陽性T_<EM>細胞とCD4陽性T_<CM>細胞の分化・生存の分子機構を解明し、T細胞免疫記憶構築の制御機構を明らかにすることを目的とした。【研究成果】T細胞副刺激分子0X40からのシグナルがCD4陽性T_<EM>細胞の分化・生存に関与し、CD4陽性T_<CM>細胞の分化・生存には関与しないことを見出した。従って、CD4陽性T_<EM>細胞分化・生存には、樹状細胞などの0X40リガンド発現細胞によって構築される細胞外環境が重要であることが示唆された。他方、記憶T細胞の自己複製機構として、恒常性維持増殖が知られる。最近、恒常性維持増殖にはTCRシグナル特異的な「急激な増殖反応」と、IL-7依存的な「緩徐な増殖反応」が独立に存在することが示された。我々は、0X40シグナルがCD4陽性記憶T細胞の「急激な増殖反応」は促進するが、「緩徐な増殖反応」には影響しないことを見出した。IL-7が「緩徐な増殖反応」のみに関与することから、0X40とIL-7が独立の機序でCD4陽性T_<EM>細胞恒常性維持増殖に関与するという我々の以前からの仮説が支持された。

  27. 炎症性腸疾患感受性遺伝子の同定と機能解析

    石井 直人, 小野 栄夫, 木内 喜孝

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2006 - 2007

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    炎症性腸疾患(IBD)は近年急激な患者数の増大が見られる重篤な疾患である。しかしながら、その原因は不明であり有効な治療法も確立されていない。我々がT細胞活性化機構の解析過程で作製した0X40L遺伝子導入マウスはC57BL/6系統依存的にIBDを自然発症する。従って、同マウスはIBD発症責任遺伝子を検索する上で極めて有用な疾患モデルである。既に、感受性系統(C57BL/6)と抵抗性系統(BALB/c)の交配マウス339匹を用いた遺伝子連鎖解析を行い、QTL解析でLod score=7.9と極めて有意なIBD発症関連遺伝子座を特定した。その部位に焦点を当てて解析を進め、同部位の候補遺伝子を70個に絞り、さらに、それら候補遺伝子の中でC57BL/6系統におけるmRNA発現がBALB/cを含む5つの疾患抵抗性系統の発現に比べて5分の1に減弱しているものを見出した。同遺伝子は受容体型タンパク質をコードしており、疾患発症と同遺伝子SNPとの相関が、単点解析(x^2検定)でp=1.2×10^<-8>であった。以上より、同遺伝子発現減少がマウスIBD発症に関与する可能性が示唆された。そこで、同遺伝子の遺伝子導入マウスを作製し、0X40L遺伝子導入マウスと交配した。その結果、同遺伝子の遺伝子導入によりIBD発症が抑制されることが明らかになった。これらの知見は、今回見いだした有力なIBD感受性候補分子が、直接的にIBD発症と関連することを示唆する。

  28. Development of therapy method target against OX40 signal for allergy or autoimmune diseases

    MURATA Kazuko, ISHI Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2005 - 2006

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    Signals through the OX40 costimulatory receptor on naive CD4 T cells are essential for full-fledged CD4 T cell activation and the generation of CD4 memory T cells. Because the ligand for OX40 is mainly expressed by APCs, including activated B cells, dendritic cells, and Langerhans cells, the OX40-0X40 ligand (OX40L) interaction has been thought to participate in T cell-APC interactions. Although several reports have revealed the expression of OX40L on T cells, the functional significance of its expression on them is still unclear. In this study, we demonstrate that Ag stimulation induced an increase in the surface expression and transcript levels of OX40L in CD4 T cells. Upon contact with OX40-expressing T cells, the cell surface expression of OX40L on CD4 T cells was markedly down-regulated, suggesting that OX40-OX40L binding occurs through a novel T cell-T cell interaction. To investigate the function of this phenomenon, we examined the proliferative response and survival of OX40L-deficient CD4 T cells when challenged with Ag. In vitro studies demonstrated markedly less CD3-induced proliferation of OX40L-deficient CD4 T cells compared with wild-type CD4 T cells. When using TCR transgenic CD4 T cells upon Ag stimulation, survival of OX40L-deficient T cells was impaired. Furthermore, we show that upon antigenic stimulation, fewer OX40L-deficient CD4 T cells than wild-type cells survived following transfer into wild-type and sublethally irradiated recipient mice. Taken together, our findings indicate that OX40L-expressing T cells have an autonomous machinery that provides OX40 signals through a T cell-T cell circuit, creating an additional mechanism for sustaining CD4 T cell longevity.

  29. A unique CD204^+ subpopulation of dendritic cells in NOD mice

    TAKAHASHI Kazuma, YOSHINORI Hinokio, ISHI Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2005 - 2006

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    Dendritic cells (DC) display defective function and phenotype in human type 1 diabetes, as well as in NOD mice and BB rats, and play crucial roles in the pathogenesis of this disease. To characterise molecular changes in bone marrow (BM)-derived DC from NOD, we compared transcript profiles of these cells with those from NON mice, and then found that BMDC from NOD express significantly higher level of CD204 than NON. Interestingly, CD204 on DC reportedly mediates a capacity to capture antigens from live cells referred to as nibbling. Strong expression of CD204 on NOD DC possibly leads to active antigen uptake from autologous cells, and then to the predisposition to autoimmunity. Focusing on this point, we here investigated the phenotype and function of CD204^+BM and splenic DC from NOD. BM cells from 6-week-old female mice were cultivated in the presence of GM-CSF and IL-4 over 6 days. CD11c^+DC were sorted by magnetic beads-conjugated anti-CD11c antibodies. DC were phenotyped by a flow cytometer. Nibbling by BMDC was evaluated by monitoring the trafficking of plasma membrane between DiO- and DiD-labeled and unlabeled cells. BMDC from NOD displayed 7 times higher mean fluorescence intensity of CD204, than normal strains (NOD 65.7±3.4, NON 8.2±0.34, C3H/HeN 8.0±0.55, Balb/c 9.0±0.49 ; P<0.05, Mann-Whitney U test). Among splenocytes, the proportion of CD204^+CD11c^+ DC from NOD was significantly higher than normal strains (NOD 0.65±0.09%, NON 0.10±0.02%, C3H/HeN 0.10± 0.02%, Balb/c 0.04±0.03% ; p<0.05). The phenotypes of CD204^+CDllc^+ BM and splenic DC were CD4^<low>CD8^-CD11b^<low>CD16/32^+CD19^<low>CD80^<high>CD86^<high>MHCclassI^+classII^+F4/80^+Gr-1^<low>. Unlabeled BMDC from NOD acquired fluorescently dual labeled membrane from other cells more rapidly than those from NON. We propose that CD204 highly expressed in a unique subpopulation of DC from NOD possibly leads to active uptake of self-antigens, and then to the predisposition to autoimmune diseases in NOD.

  30. CD4陽性記憶T細胞恒常性維持におけるOX40の役割

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2005 - 2006

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    目的:免疫記憶を理解する上で記憶T細胞の成立・維持機構の解明は重要な研究課題である。特に、CD4陽性記憶T細胞の成立・維持の機構の解析はCD8+T細胞のそれに比べてほとんど進んでいない。他方、以前より、OX40-OX40LがCD4陽性記憶T細胞の成立に関与することは知られていたが、その機序については全く不明である。本研究により、CD4陽性記憶T細胞成立・維持におけるOX40の役割を明らかにする。 結果・考察:記憶T細胞の成立には、CD4,CD8に関わらず、前期の抗原依存性過程と後期の抗原非依存性過程が存在することが知られる。後者の過程はサイトカインなどに依存するT細胞恒常性維持増殖(homeostatic proliferation)と呼ばれる現象と同一である。これまで、T細胞補助シグナル分子のT細胞恒常性維持増殖への関与を否定する報告が相次いでいたが、我々は、CD4陽性T細胞移入実験系において、OX40シグナルがCD4陽性T細胞恒常性維持増殖に促進的に機能することを見出した。次に、上記CD4陽性T細胞移入実験において阻害性抗OX40L抗体および抗IL-7受容体抗体投与を行ったところ、どちらかの単独投与によりCD4陽性エフェクター記憶T細胞の恒常性維持増殖が抑制され、さらに両者の投与では完全に抑制された。一方、CD4陽性ナイーブT細胞恒常性維持増殖は、抗IL-7受容体抗体投与のみでほぼ完全に抑制され、上記のようなOX40とIL-7シグナルの相加効果は見られなかった。従って、CD4陽性T細胞恒常性維持増殖におけるOX40とIL-7シグナルの役割は、ナイーブT細胞とエフェクター記憶T細胞とで異なる可能性が示唆された。

  31. Functional and therapeutic study on inhibitory genes associated with collagen diseases

    ONO Masao, ISHII Naoto, FURUKAWA Hiroshi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2004 - 2006

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    We have identified two mutant genes that individually cure autoimmune diseases in murine models [1,2]. Futhermore, by using two mutant strains of mice with these mutations, we attempted to identify effecter cells and molecules critically involved in the pathogenesis of autoimmune diseases in mouse models, MRL/lpr and EOD. The results provided new understandings as follows : 1.The role of signal lymphocyte activation molecule (SLAM)-associated protein (SAP) in the development, of autoimmunity (Furukawa, Ono, Ishii). Concanavalin A (ConA)-induced hepatitis, which is known as a model for autoimmune hepatitis, was investigated in wild-type and SAP-deficient strains of mice. The results provided evidences that (1)SAP has a role for suppression of the development of ConA-induced hepatitis, and that (2)the suppressive effect of SAP depends upon a cellular function for hepatic injury, which is independent of Fas ligand (FasL) 2.Characterization of SLAM-family receptors associated With the development autoimmune diseases in mice (Furukawa, Ono). We constructed DNA vectors that SLAM-family receptors expressed in vivo and determined an optimal condition of the hydrostatic expression method for each of the expression construct. Effect of induced expression of each SLAM- family receptor in autoimmune mice is on investigation, 3.Identification of platelet function for the development of allergic reaction in mice (Ono). We established C57BL/6J-cinn/cinn (B6^<cinn>), a congenic strain that shows a defect in platelet functions by a loss-of- function mutation on Cuppuccino gene (Cno). In B6^<cinn> mice significantly higher anaphylactic response to passive IgE challenge (IgE anaphylaxis) was observed than in wild-type mice. The difference was apparent especially in late phase of the reaction. It is indicated that platelet play a role in the recovery from IgE, anaphylaxis. 4.Identifieation of platelet function for the development of experimental and spontaneous arthritis in mice (Ono). In our preliminary study, B6^<cinn> showed resistant phenotype in collagen-induced arthritis (CIA), suggesting that platelet has a suppressive role in the development of CIA.

  32. Signal transducing pathways in immune cells and immunological disorders caused by their dysfunctions

    SUGAMURA Kazuo, ISHII Naoto, TANAKA Nobuyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (S)

    Institution: Tohoku University

    2002 - 2006

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    1.Immune regulation by intracellular vesicular trafficking STAM1 and STAM2 are required for the ubitquitin-dependent sorting of protein cargos into multivesicular bodies. Using genetically manipulated mice, in which both STAM1 and STAM2 are lacking specifically in dendritic cells, we found that STAM1/2 play an important role in antigen presentation. In vitro analyses demonstrated that STAM1/2-double KO dendritic cells show aberrant intracellular localization of MHC II and overexpression of surface MHC II. Therefore, STAM1/2 is thought to critically regulate MHC II trafficking from intracellular vesicular compartments to the plasma membrane. 2.Autoimmune diseases mediated by T cell costimulatory signals We previously reported that mice overexpressing OX40 ligand (OX4OL), which is a T-cell-costimulatory molecule expressed by antigen presenting cells, spontaneously develop IBD. A mechanism for IBD development in the OX40L-transgenic (Tg) mice may be mediated by excessive OX40 signals in CD4^+ T cells because deliberate OX40-0X4OL interaction makes effector CD4^+ T cells insensitive to regulatory-T-cell-mediated suppression, which is an important mechanism to maintain the homeostasis of mucosal immunity. Although this abnormal T cell response in OX40L-Tg mice was seen in all the mouse strains we used, IBD develops in a C57BL/6 strain-dependent manner. Thus, we have attempted to identify susceptibility genes for IBD seen in OX40L-Tg mice. A QTL analysis using the susceptible strain (C57BL/6) and a resistant strain (BALB/c) revealed three disease-associated loci on Ch. 4,Ch. 8,and Ch. 19. From these loci, we have identified a candidate susceptibility gene for IBD.

  33. 成人T細胞白血病における白血病細胞起源に関する研究

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2005 - 2005

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    12例のATL患者由来新鮮白血病細胞、2種のATL細胞株、4種のHTLV-I感染T細胞株のFoxp3 mRNA量をreal-time PCR法で測定した。その結果、5例の新鮮ATL細胞とHTLV-I感染T細胞株MT-2にFoxp3の高発現を認めた。さらにFoxp3高発現ATL細胞中2例とMT-2細胞にT細胞反応抑制効果を認めた。抑制効果がみられたそれら細胞の抑制効果はTreg細胞と同様に細胞-細胞接触依存的であることが分かった。以上より、Foxp3高発現のATL細胞2例とMT-2細胞がTreg細胞類似であることが明らかになった。他方、ヒトT細胞株Jurkat(Foxp3陰性)にHTLV-I p40taxを誘導したが、Foxp3の発現は誘導されなかった。さらに、IL-2存在下にCD25^+CD4^+T細胞(Treg細胞)およびCD25^-CD4^+T細胞(通常のT細胞)をそれぞれ放射線照射MT-2と共培養し、HTLV-I感染を行ったが、両細胞集団間でウイルス感染効率に有意な差は認めなかった。IL-2非存在下に同一の実験を行ったところCD25^-CD4^+T細胞由来のHTLV-I感染細胞が2クロン、Treg細胞由来のHTLV-I感染細胞が3クロン樹立された。それぞれの由来クロンでのFoxp3発現を測定したところ、CD25^-CD4^+T細胞由来細胞ではFoxp3発現は低値のままであった。HTLV-I感染およびp40tax発現によってT細胞にFoxp3発現が誘導されないことから、Foxp3高発現のATL細胞は、Foxp3高発現T細胞由来すなわちTreg細胞由来であると考えられた。

  34. Regulation of infectious immunity by the OX40-0X4OL system

    SUGAMURA Kazuo, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research on Priority Areas

    Institution: Tohoku University

    2001 - 2005

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    OX40-0X4OL interactions regulate survival and homeostasis of CD4+ T cells. Furthermore, several reports have demonstrated that OX40 signaling in T cells mediates not only autoimmune/inflammatory responses, but also infectious immunity by regulating T cell immunity. Interestingly, C57BL/6 OX40L-transgenic mice, which were constructed by using mouse lck proximal promoter, showed susceptibility to L. major infection although C57BL/6 wild-type mice are resistant to the infection. Since IL-13-deficiency in OX40L-transgenic mice recovered the susceptibility, IL-13 production induced by OX40 signals may mediates the susceptibility to L. major infection. In addition, OX40L-transgenic mice spontaneously develop organ-specific immune-associated diseases, namely interstitial pneumonia and inflammatory bowel disease (IBD). Studies using the OX40L-transgenic mice have demonstrated that OX40 signaling prominently affected the sensitivity of T cells to CD25+ regulatory-T-cell-mediated suppression, leading to IBD. Further investigation revealed that the development of IBD requires intestinal bacterial flora. Interestingly, IBD develops in a C57BL/6 strain-dependent manner. Thus, we have attempted to identify susceptibility genes for IBD seen in OX40L-Tg mice. A QTL analysis using the susceptible strain (C57BL/6) and a resistant strain (BALB/c) revealed a susceptibility locus on Ch. 4, which is syntenic to a human IBD-susceptibility locus (IBD7). These results suggest that a certain gene in this locus contributes to IBD development, which is associated with intestinal immunity to the bacterial flora.

  35. 間質性肺炎および炎症性腸疾患責任遺伝子の同定

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2004 - 2004

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    間質性肺炎および炎症性腸疾患(IBD)はともに原因不明の重篤な疾患である。本研究者が作製したOX40L遺伝子導入(Tg)マウスはC57BL/6(B6)系統依存的に間質性肺炎とIBDを加齢とともに自然発症する。BALB/cなどの他の系統では全く発症せず、すなわちヒト疾患と同様に特定の遺伝背景依存的な疾患発症を示す。従って、OX40L遺伝子導入で疾患を発症する感受性系統と疾患を発症しない抵抗性系統を交配することによって、間質性肺炎およびIBDの感受性遺伝子を同定することが可能になる。本研究の目的は、マウスにおける上記2疾患の感受性/抵抗性遺伝子の同定である。 疾患感受性であるB6背景OX40L-Tgマウスを疾患抵抗性マウス系統であるBALB/cマウスと交配し、((B6xBALB/c)F1xB6)N2マウスを900匹作製した。N2マウスのうちで遺伝子型がOX40L-Tgマウス(350匹)を抽出し、B6系統OX40L-Tgマウスが100%疾患を発症する20週齢に達した時点で、疾患発症の有無を検索した。その結果、B6-N2-OX40L-Tgマウスの3分の2に間質性肺炎とIBDの発症を認めた。そこで疾患重症度を指標とした遺伝子連鎖解析を行い、間質性肺炎発症関連遺伝子座1ヶ所とIBD発症関連遺伝子座3カ所を同定した。IBD発症関連遺伝子座の1ヶ所についてはその部位の遺伝子型と疾患発症の有無との相関が、χ^2検定でP<10^<-7>と、極めて有意であった。加えて、同部位がヒトIBD感受性遺伝子座として報告されている部位と完全に一致することが判明した。そこで、疾患感受性系統と抵抗性系統の2系統マウス間で同部位に存在する遺伝子群の塩基配列の相違を比較したところ、IBD発症を規定する有力な候補遺伝子が同定された。

  36. Immunological tolerance regulated by the interaction between T cell and antigen-presenting cell

    ISHII Naoto, ASAO Hironobu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2003 - 2004

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    The presence of OX40^+ lymphocytes and OX40 ligand^+ (OX40L)^+ cells at the sites of inflammation in T cell-mediated disorders, such as autoimmunity, allergic and infectious diseases, and GVHD is well documented. These observations suggest important roles for OX40-OX40L interactions in immune disorders. CD25^+CD4^+ regulatory T (Treg) cells suppress autoinununity by controlling peripheral self-reactive T cell activation. Recently, several reports have revealed that OX40 is preferentially expressed on Treg cells in terms of mRNA and protein expression in mice. Thus we examined whether OX40-OX40L interaction may control Treg cell function that are essential for preventing autoimmunity. We found by using OX40L-deificient mice and mice overexpressing OX40L that CD25^-CD4^+ T cells became insensitive to Treg-mediated suppression when they were exposed to OX40L-expressing cells, or when they were treated with an agonistic OX40-specific monoclonal antibody. OX40 signaling could also abrogate the disease-preventing activity of Treg cells in an experimental model of inflammatory bowel disease using RAG2-deficient mice that expressed different levels of OX40L. Thus, these data show that OX40 signals can oppose Treg-mediated suppression when they are delivered directly to antigen-engaged naive T cells. Taken together, OX40 signaling directly control Treg-cell-mediated immune suppression.

  37. T細胞補助刺激分子を介した調節性T細胞機能制御

    石井 直人, 浅尾 裕信

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 萌芽研究

    Institution: 東北大学

    2003 - 2003

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    自己免疫疾患やアレルギーは免疫寛容機構によって防御されているが、免疫寛容が破綻すると、それら疾患が発症すると考えられている。しかし、免疫寛容維持と破綻の分子機構の詳細は明らかではない。我々は最近、T細胞副刺激分子であるOX40が免疫寛容破綻に直接的に関与する可能性を示した。そこで、OX40シグナルによるT細胞免疫寛容破綻機構の解明を目的として、本研究を実施した。CD25陽性CD4陽性制御性(Treg)T細胞はT細胞活性化を抑制することにより、生体の免疫寛容を維持する。Treg細胞が恒常的にOX40を発現することから、Treg細胞機能とOX40シグナルに何らかの関連性があると考え、OX40L発現抗原提示細胞(APC)存在下でのTreg細胞機能を検討した。その結果、野生型マウス由来APC存在下ではT細胞活性化抑制効果を発揮したTreg細胞が、OX40L-Tgマウス由来APC存在下では全く抑制効果が発揮できないことを見いだした。さらに、CD25陰性CD4陽性T細胞とTreg細胞をRAG2欠損マウスに移植し、生体内でのTreg細胞機能を検討した。RAG2欠損マウスにCD25陰性CD4陽性T細胞のみを移入すると炎症性腸疾患を発症するが、Treg細胞を共移入すると、Treg細胞の免疫寛容維持機能により疾患発症が完全に抑制される。ところが、OX40L-Tg/RAG2欠損マウス内ではTreg細胞を共移入しても、全く腸疾患発症は抑制できないことが分かった。すなわちin vivoにおいても過剰なOX40-OX40L結合がTreg細胞機能を破綻させた。以上の結果より、OX40刺激による免疫寛容破綻のひとつの機序として、Treg細胞依存性免疫寛容解除が関与していることが分かった。さらにOX40L過剰刺激はがん免疫を増強することが示された。

  38. がん免疫における生体内免疫寛容制御機構の解明

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2003 - 2003

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    生体は自己のがん細胞に対して免疫寛容となっている。しかしながら、免疫寛容維持と破綻の分子機構は明らかではなく、その解明はがん免疫制御において重要な研究課題である。我々は最近、T細胞副刺激分子であるOX40が免疫寛容破綻に直接的に関与する可能性を示した。そこで、OX40シグナルによるT細胞免疫寛容破綻機構の解明を目的として、本研究を実施した。CD25陽性CD4陽性制御性(Treg)T細胞はT細胞活性化を抑制することにより、生体の免疫寛容を維持する。マウスにおいて人為的にその細胞集団を除去すると、自己免疫発症を促すばかりでなく、がん免疫を増強することが知られている。Treg細胞が恒常的にOX40を発現することから、Treg細胞機能とOX40シグナルに何らかの関連性があると考え、OX40L発現抗原提示細胞(APC)存在下でのTreg細胞機能を検討した。その結果、野生型マウス由来APC存在下ではT細胞活性化抑制効果を発揮したTreg細胞が、OX40L-Tgマウス由来APC存在下では全く抑制効果が発揮できないことを見いだした。さらに、OX40L-Tg-RAG2欠損マウス(各組織にOX40L高発現したリンパ球欠損マウス)にTreg細胞と通常のCD4陽性T細胞を移入したところ、in vivoにおいても抑制機能が発揮できないことが分かった。他のグループの報告によりTreg細胞関連免疫寛容ががん免疫をも抑制することが明らかにされていることから、人為的OX40刺激によりがん免疫を増強できる可能性が高い。実際に、マウスにメラノーマ細胞を移植・腫瘍形成後に、腫瘍内にウイルスベクターを用いてOX40L遺伝子を導入すると、腫瘍増殖速度が著しく抑制されることが分かった。OX40刺激はがん免疫を増強することが明らかになった。

  39. 間質性肺炎および炎症性腸疾患感受性遺伝子の同定

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2003 - 2003

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    本研究者が作製したOX40L遺伝子導入(Tg)マウスはC57BL/6系統依存的に炎症性腸疾患(IBD)および間質性肺炎を加齢とともに自然発症する。DBA/2やBALD/c系統では全く発症せず、すなわちヒト疾患と同様な特定遺伝背景依存的な発症を示す。従って、OX40L遺伝子導入で疾患を発症する感受性系統と疾患を発症しない抵抗性系統を交配することによって、間質性肺炎およびIBDの感受性遺伝子を同定することが可能になる。本研究では、通常の遺伝子連鎖解析法に則ってマウスにおける上記2疾患の感受性/抵抗性遺伝子を同定する。今年度は、疾患感受性であるC57B/6遺伝子背景OX40L-Tgマウスを疾患抵抗性マウス系統であるBALB/cマウスと交配し、交雑F2を約600匹作成した。F2マウスのうちでOX40L-Tgマウスのみ(300匹)を解析対象とし、疾患が発症する20週齢以後に上記2疾患の発症の有無を判定する。現在、各個体の疾患発症の有無を検索中である。 一方、IBDの発症とOX40シグナルの関連性を明らかにするためにクローン病マウスモデルとして知られる実験的IBDを施行した。RAG2欠損マウスにCD25陰性CD4陽性T細胞のみを移入するとクローン病様IBDを発症するが、CD25陽性制御性(Treg)T細胞を共移入すると、Treg細胞の免疫寛容維持機能により疾患発症が完全に抑制される。ところが、OX40L-Tg/RAG2欠損マウスではTreg細胞を共移入しても、IBD発症を全く抑制できなかった。以上の結果より、OX40L-TgマウスにおけるIBD発症のひとつの機序として、OX40L過剰(あるいは異所性)発現がTreg細胞依存性免疫寛容を破綻させる可能性が示唆された。

  40. OX40-OX40リガンド系を介した免疫制御

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究

    Institution: 東北大学

    2001 - 2002

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    (研究目的)OX40はTNF受容体ファミリーに属する分子で、活性化T細胞上に発現しT細胞補助刺激分子として機能する。一方、そのリガンドであるOX40Lは樹状細胞などの抗原提示細胞上に発現し、T細胞上のOX40と結合することによりT細胞にOX40刺激を与える。OX40/OX40L系の生体内機能を明らかにするためにOX40L遺伝子欠損マウスおよびOX40L遺伝子導入マウスを作製し、種々の免疫反応を解析した。 (研究成果と考察) 上記OX40L遺伝子改変マウスを用いて、接触性皮膚過敏反応を試みたところ、OX40L遺伝子欠損マウスでは反応が抑制され、OX40L-Tgマウスでは反応が強く増強された。アレルゲン感作マウスリンパ節より活性化ランゲルハンス細胞(LC)を単離し、OX40Lの発現を検討したところ、アレルゲン感作依存性にOX40Lの発現が観察された。さらにマウス皮膚より未感作LCを単離し、アロ抗原反応性T細胞活性化能を測定したところ、OX40L遺伝子欠損LCの抗原提示能は抑制傾向を呈し、OX40L-Tgランゲルハンス細胞はその機能が強く亢進していた。以上より、OX40Lが皮膚ランゲルハンス細胞機能において重要な役割を有していることが明らかになった。他方、OX40L-TgマウスをC57BL/6系統に戻し交配したところ、抗DNA抗体の上昇を伴う間質性肺炎と炎症成長疾患を自然発症することが明らかになった。この発症はC57BL/6系統特異的であった。さらに、OX40L-TgマウスのCD4陽性T細胞をRAG2欠損マウスに移入したところ、組織学的に同一の疾患が再現された。これらの結果は疾患発症が自己免疫機序である可能性を示唆する。一方、OX40L-Tgマウスでは可溶性蛋白抗原投与によって誘導されるはずの免疫寛容が全く誘導されず、末梢性T細胞免疫寛容が破綻していることが判明した。以上の結果より、OX40-OX40L系が免疫寛容制御に関与し、自己免疫発症と密接に関わる可能性が示唆された。

  41. 腫瘍免疫におけるOX40-OX40L系の機能解析

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(C)

    Institution: 東北大学

    2001 - 2001

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    T細胞活性化における副刺激伝達分子であるOX40(CD134)はTNF受容体ファミリーの1つで、そのリガンド(OX40L)は抗原提示細胞特異的に発現する。OX40L欠損マウスおよびOX40L遺伝子導入(Tg)マウスを作製し、蛋白抗原特異的記憶T細胞機能を解析したところ、OX40LがCD4陽性T細胞活性化における抗原提示細胞機能に必須であることが明らかになった。次に、これらマウスにおけるアロ抗原に対するCTL活性およびNK活性を検討したところ、OX40L-Tgマウスにおいてそれら活性の著しい低下が観察された。しかしながら、上記マウスに悪性黒色腫細胞株B16-F10を皮下移植あるいは静注を行ってその腫瘍免疫機能を検討したが、野生型ヤウスに比して有意な免疫異常は確認されなかった。他のがん細胞株を用いて同様の実験を継続している。従来、OX40シグナルはT細胞活性化に対して促進的に機能すると考えられており、現在のところOX40L-TgマウスにおけるCTLおよびNK細胞活性化障害のメカニズムについては不明である。今後の研究課題である。 一方、腫瘍細胞特異的ヒトCTLクロンを長期培養により樹立し、そのOX40、OX40Lの発現を解析した。その結果、従来抗原提示細胞特異的に発現すると考えられていたOX40Lが、抗原刺激依存的にT細胞上に発現誘導されることが明らかになった。この結果は長期生存記憶T細胞の機能にOX40/OX40L系がオートクライン的に関与する可能性を示唆する。現在、腫瘍細胞特異的ヒトCTLの機能におけるOX40L/OX40系の役割について解析中である。

  42. アレルギー免疫疾患モデルマウスを用いた発症要因に関わる遺伝背景の解析

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(C)

    Institution: 東北大学

    2001 - 2001

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    OX40(CD134)はTNF受容体ファミリーの1つで、そのリガンド(OX40L)は我々がHTLVF-I・Taxの転写標的遺伝子として単離したn型受容体蛋白gp34である。OX40はT細胞活性化における副刺激伝達分子の1つで、慢性関節リウマチなどの種々のアレルギー・自己免疫特異的T細胞に発現することが知られているが、自己免疫発症におけるOX40/OX40L系の機能的役割は未解明である。我々は最近、QX40L遺伝子導入(Tg)マウスを作製した。同TgマウスをC57BL/6に戻し交配したところ、個体レベルでTh2反応優位の表現型を呈し、Leishmania major感染に対して感受性となった。一方、同QX40-LTgマウスは生後10週頃より、大腸炎、間質性肺炎を発症し、加齢とともに発症率は100%となった。それらの組織からはサイトメガロウイルス、カリニ原虫などの既知の病原体は検出されず、自己免疫機序で惹起された病変であることが示唆された。特発性間質性肺炎はヒト膠原病の合併症として重大な疾患であるが、これまでマウスにおける自然発症モデルが存在せず、その発症機序の詳細も明らかではない。現在、OX40L-Tgマウスにおける間質性肺炎発症機序を解明し、ヒト膠原病合併間質性肺炎のモデルとなりうるかどうかを検討中である。また、DBF1やBALB/c遺伝背景のOX40L-Tgマウスでは明らかな症状がみられないことから、上記の自己免疫発症はマウスの遺伝背景依存的であると考えられる。

  43. Regulation of autoimmune diseases by OX40-OX40L interact

    SUGAMURA Kazuo, ISHII Naoto, ASAO Hironobu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2000 - 2001

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    OX40L expressed on APCs, and its receptor, OX40 present on activated T cells, are members of the TNFR/TNF family respectively and have been located at the sites of inflammatory conditions. We have observed in OX40L-deficient mice, an impaired APC capacity, and by targeting this interaction a reduction in the symptoms of several autoimmune disorders in mice. In addition, OX40/OX40L signals are suggested to be implicated in peripheral T cell tolerance, which is a mechanism to limit autoimmunity. We have recently established OX40L transgenic (Tg) mice by using a T cell specific promoter. In these mice, failed induction of peripheral CD4^+ T-cell tolerance was observed. In addition, the OX40L-Tg mice spontaneously developed interstitial pneumonia and inflammatory bowel disease. Such autoimmune diseases were observed in OX40L-Tg mice on the C57BL/6 background but not BALB/c or DBA/1J, suggesting mice strain dependency of the disease onset. Furthermore, these diseases were completely reconstituted in Rag 2-deficient mice by introduction of OX40L-Tg CD4+ T cells and blocking of OX40/OX40L interaction completely prevented initiation of the diseases. Our findings implicate that OX40/OX4 interactions may be a vital link in a trigger of organ-specific autoimmunity.

  44. Cytokine receptor γc chain/Jak3 mediated signal transduction and analysis of immunodeficiecy by dysfunction of the γc chain/Jak3

    TAKESHITA Toshikazu, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Shinshu University

    2000 - 2001

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    We identified and have characterized the interleukin 2 receptor γ chain (IL-2Rγ ), of which mutations cause Human X-linked severe combined immunodeficiency disease ( XSCID ), a disease that occurs in as many as 50 % of patients with primary SCID. It was found that mutations of Jak3, which is associated with and mediates the down stream signal transduction from the γ chain, also caused autosomal recessive SCID. Thus, we considered the possibility that there is the novel gene related to SCID down stream of Jak3 and then originally identified novel Jak3 substrates including STAM. In this study, using the gene targeting and transgenic mice we analyzed the in vivo function of the molecules to determine its involvement in the signal transduction pathway from γ chain /Jak3. ( 1 ) Double deficient mice, lacking both STAM1 and STAM2, were embryonically lethal. To further elucidate the function of STAM in lymphocytes, we established conditionally targeting mice that will lack of both molecules in lymphocytes ( 2 ) Hgs knockout ( KO ) mice showed significantly decreased response to stimulation with transforming growth factor-β ( TGF-β ) family molecules. ( 3 ) AMSH-deficient mice exhibited postnatal growth, retardation and died between day 19 and 23. The neurons were defect in the subfield of hippocampus of AMSH-deficient mice. ( 4 ) The total number of thymocytes were reduced in the transgenic mice expressing Graf40 mutant, whereas it was significantly increased in the double-negative thymocytes subset.

  45. Analysis of transgenic mice expressing human parvovirus non-stractual (NS1) protein

    SUGAMURA Kazuo, ISHII Naoto, ASAO Hironobu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2000 - 2001

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    Human parvovirus B19 is the cause of several distinct clinical syndromes. The most common is erythema infectiosum (fifth disease), a febrile exanthem occurring primarily in children. Recent studies have shown that parvovirus B19 can cause acute arthritis and occasionally a chronic arthropathy, both in children and adults. In this study, we generated transgenic mice expressing a viral non-structural (NS1) protein and analyzed its functional importance. Most of the transgenic mice died at the embryonic stage, some of which developed hydropic changes caused by severe anaemia at embryonic day 15.5 (E15.5). Histological examination of embryos at E15.5 showed significantly fewer erythropoietic islands in the liver parenchyma, whereas their hearts showed no abnormal signs, such as cardiomegaly and apoptotic cells. The NS1-transgenic mouse lines established here provide an animal model for human NIHF (non-immune hydrops fetalis) and suggest that NS1 plays a crucial role in the adverse outcome associated with intrauterine B19 infection in humans. Furthermore, we demonstrate that erythroblastoid UT7/Epo cells infected with B19 virus fall into growth arrest with 4N DNA, indicating G(2)/M arrest. These B19 virus-infected cells displayed accumulation of cyclin A, cyclin B1, and phosphorylated cdc2 and were accompanied by an up-regulation in the kinase activity of the cdc2-cyclin B1 complex, similar to that in cells treated with the mitotic inhibitor. However, degradation of nuclear lamina and phosphorylation of histone H3 and H1 were not seen in B19 virus-infected cells, indicating that the infected cells do not enter the M phase. Accumulation of cyclin B1 was persistently localized in the cytoplasm, but not in the nucleus, suggesting that B19 virus infection of erythroid cells raises suppression of nuclear import of cyclin B1, resulting in cell cycle arrest at the G(2) phase. The B19 virus-induced G(2)/M arrest may be the critical event hi the damage of erythroid progenitor cells seen in patients with B19 virus infection.

  46. アレルギー免疫疾患モデルマウスを用いた発症要因に関わる遺伝背景の解析

    石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(C)

    Institution: 東北大学

    2000 - 2000

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    <背景と目的> OX40リガンド(OX40L)は我々が遺伝子単離した免疫分子で、TNFファミリーに属する。最近、抗原提示細胞上のOX40Lなどの機能分子の発現がアレルギーや自己免疫などの発症に関与していることが示唆され、その発症要因としてMHC以外の遺伝素因が注目されている。そこで我々はOX40L遺伝子欠損(KO)マウスおよびOX40Lトランスジェニンク(Tg)マウスを作製し、自己免疫病モデルである実験的自己免疫性脳脊髄炎(EAE)に適用し、OX40Lの自己免疫発症への関与を検討した。従来、アレルギー・自己免疫発症の遺伝的背景としてリンパ球機能分子が想定されていたが、本研究では、OX40Lを含む抗原提示細胞機能分子に着目し、自己免疫発症遺伝素因を解明する。 <結果・考察> 1.抗原提示細胞にOX40Lを過剰に発現したTgマウスでは、EAEが野生型に比し重症化し、一方OX40L欠損マウスではEAEの発症が強く抑えられた。OX40Lが自己免疫発症に直接的に関与することが明らかになった。 2.Leishmania Major(LM)はマウスの免疫反応解析に用いられる代表的な寄生虫である。LMは、感染させるマウスの遺伝背景の違い(C57BL/6とBalb/c)により、免疫反応が大きく異なることが知られている。LM耐性マウスであるC57BL/6にOX40Lを過剰発現するとLMに感受性となり、一方LM感受性マウスであるBALB/cでOX40を欠損させるとLM感染に耐性となった。これらの事実は、寄生虫感染アレルギー反応において、OX40Lが特定の遺伝的素因と機能的に関連しつつ疾患発症に重要な機能を有している可能性が示唆された。BALB/cマウスのLM感受性遺伝子は12番染色体上に想定されており、OX40Lのそれ(1番)とは異なる。さらに詳細な解析が必要である。

  47. 新規シグナル分子"AMSH"の遺伝子欠損による脳神経特異的なアポトーシス誘導

    浅尾 裕信, 石井 直人

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(A)

    Institution: 東北大学

    2000 - 2000

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    STAM1は種々のサイトカインによりチロシンリン酸化を受けるアダプター分子である(Immunity.,6,449-457,1997),さらにSTAM1 SH3領域に会合する分子として我々はAMSHを単離同定した(J.Biol.Chem.,274,19129-19135,1999)。AMSHの機能を検索する目的でAMSH欠損マウスを作出した結果、AMSHホモ欠損マウスはほぼ正常に生まれてくるが、生後10日以降より成長遅延、末梢神経反射異常、眼瞼下垂等の異常を呈し、生後3週で100%死亡した。同マウスの組織像を検索した結果、脳以外の主要な組織に明らかな異常を認めず、誕生直後では脳組織も正常であった。しかし、生後7日頃より大脳皮質、顔面神経核、海馬等の脳神経組織特異的に細胞死を認めた。この時期に低血糖やアシドーシスはないことから、AMSH欠損マウスの神経細胞死は一次的なものと考えられる。また、アポトーシスは小脳組織では認められず、脳神経細胞の一部のポピュレーションに特異的であることが示唆された。正常マウス脳組織におけるAMSHの発現をin situ hybridization法にて解析したところ、海馬、大脳皮質、小脳顆粒細胞層に一致して発現がみられた。その発現強度は胎生期に強く、生後15日まである程度認められたが、生後10週では胎生期の10分の1程度であった。すなわち、AMSH発現がある程度強い時期に一致して、AMSH欠損マウスの脳神経細胞死が観察された。AMSH欠損マウス胎児脳組織を用いた初代神経細胞培養を行ったところ、常法では数日以内に細胞が死滅し、in vitroでも細胞死の促進が観察された。リンパ球、線維芽細胞の初代培養においては、AMSH欠損による細胞死増強は観察されず、AMSH欠損による細胞死誘導は神経細胞特異的である(論文投稿中)。

  48. Immune regulation by OX40/OX40 ligand system

    ISHII Naoto, ASAO Hironobu

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    1999 - 2000

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    OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L mAb, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-IgM stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice, engendered apparent suppression of the recall reaction of T cells primed with both protein- and allo-antigens and a significant reduction in KLH-specific IgG production. The impaired T-cell-priming was also accompanied by a concomitant reduction of both Th1 and Th2 cytokines. Furthermore, antigen presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo. Furthermore, we examined the effect of OX40L-deficiency or blockade of OX40-OX40L interaction in pathogenesis of experimental autoimmune encephalitis (EAE), which is a mouse model for human multiple sclerosis. OX40L-deficient and MGP34-treated mice showed less symptoms and rapid recovery during EAE as compared with wild type or control Ab-treated mice. These results suggest that OX40L may be functionally involved in the pathogenesis of autoimmune diseases such as EAE.

  49. Grf40, A Novel Grb2 Family Member, Is Involved in T Cell Signaling

    ASAO Hironobu, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    1999 - 2000

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    We molecularly cloned a new Grb2 family member, named Grf40. Expression of Grf40 is predominant in hematopoietic cells, particularly T cells. Grf40 binds tp SLP-76 more tightly than Grb2. Incidentally, Grf40 binds to linker for activation of T cells (LAT) possibly via its SH2 domain. Overexpression of wild-type Grf40 in Jurkat cells induced a significant increase of SLP-76-dependent interleukin (IL)-2 promoter and nuclear factor of activated T cell (NF-AT) activation upon T cell receptor (TCR) stimulation, whereas the C-terminal SH3-deleted Grf40 mutant lacked any recognizable increase in IL-2 promoter activity. Furthermore, the SH2-deleted Grf40 mutant (Grf40-dSH2) led to a marked inhibition of these regulatory activities, the effect of which is apparently stronger than that of the SH2-deleted Grb2 mutant. Our data suggest that Grf40 is an adaptor molecule involved in TCR-mediated signaling through a more efficient interaction than Grb2 with SLP-76 and LAT.To investigate an in vivo function of Grf40, We generated transgenic mice expressing Grf40-dSH2, which is driven by the lck proximal promoter. The total number of thymocytes was profoundly reduced in the transgenic mice, whereas in the double-negative (CD4-CD8-) thymocyte subset, in particular, the CD25+CD44-pre-T cell population was significantly increased. However, CD5 expression, which is mediated by pre-TCR stimulation, was significantly suppressed on the CD4-CD8-thymocytes of the transgenic mice. Furthermore, the SLP-76-dependent signaling was markedly suppressed as well. These data suggest that Grf40 plays an important role in the pre-TCR as well as TCR signaling in thymocytes.

  50. Cytokine receptor γc chain mediated signal transduction and analysis of immunodeficiency by dysfunction of the γc chain

    TAKESHITA Toshokazu, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    1998 - 1999

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    The interleukin 2 receptor γ chain (IL-2Rγ ), which we previously cloned, is known to be a causative gene for human X-linked severe combined immunodeficiency (X-SCID). X-SCID is a disease that occurs in as many as 50% of patients with primary SCID, and is characterized with profound defect of T and NK cells and impairment of B cell differentiation. The IL-2Rγ is shared among the receptors for several cytokines, and called the common γ(γc) chain. The cytoplasmic domain of the γc chain is associated with Jak3 tyrosine kinase, of which mutantions also cause an autosomal recessive SCID, Jak3-SCID. These observations suggest that the γc/Jak3 signaling pathway is indispensable for development of T, NK and B cells. We thus hypothesized that molecules involved in the γc/Jak3 signaling pathway may include causative gene products for SCID. In this context, we have identified STAM1, which is associated with Jak3 and Jak2, and involved in signaling for cell proliferation and c-myc induction mediated by IL-2 and GM-CSF. STAM1 knockout mice were born and developed normally, but their body weights decreased gradually after 5 weeks of age, and were below 60-70% of those of normal mice. 90% of the mice died before 16 weeks of age. Until 4 weeks of age, STAM1 knockout mice were normal clinically, but histopathologically they showed an abnormality in the CA3 region of the hippocampus. On the other hand, we molecularly cloned a STAM1 homologous molecule named STAM2, and revealed that STAM2 has similar in vitro functions to STAM1, suggesting that STAM1 may be compensated by STAM2 in the STAM1 knockout mice. We have also developed STAM2 knockout mice, which show normal growth and no abnormal features so far. We are now attempting to establish double KO mice for STAM1 and STAM2 to examine their possible functional relationship.

  51. Establishment of Model Mice of Rheumatoid Arthritis by using nonstructural protein 1 (NS1) of parvovirus B19

    SUGAMURA Kazuo, ASAO Hironobu, ISHII Naoto

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    1998 - 1999

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    Human parvovirus B19 (B19) infection causes a wide variety of human diseases including erythema infectiosum, aplastic crises and nonimmune hydrops fetalis (NIHF). Epidemiological studies of B19 virus has suggested a possible relationship between B19 infection and rheumatoid arthritis (RA). Since B19 virus produces one major nonstructural protein, NS1, which is known to harbor functions of apoptotic cytotoxicity and transcriptional activator, we suspect that NS1 plays an important role in the occurrence of infectious diseases caused by B19 virus. In this research project, we attempted to generate NS1 transgenic mice, which develop NHIF and RA. We first generated transgenic mice of NS1, of which expression is controlled by the GATA1-promoter. A line of NS1-Tg mice showed embryonic lethality within E6.5, and two other lines were also embryonically lethal between E14.5 and E15.5 with severe anemias. These phenotypes of NS1-Tg mice resemble those of human NIHF, suggesting that the NS1-Tg mice are a useful model for human NIHF. We also generated another type of NS1-Tg mice, in which NS1 expression is regulated by the immunoglobulin promoter in B lymphocytes. They expressed NS1 mRNA in lymphoid cells, but expression of NS1 protein was undetectable. Up until 40 weeks of age, they did not develop any signs of RA or any other autoimmune diseases. Since their expression of NS1 may be too low to induce any pathology in these mice, we are trying to generate other lines of NS1-Tg mice, which express higher amounts of NS1.

  52. サイトカイン受容体を介する新たな増殖シグナル伝達経路“Jak-STAM"

    竹下 敏一, 石井 直人, 田中 伸幸

    Offer Organization: 日本学術振興会

    System: 科学研究費助成事業

    Category: 特定領域研究(A)

    Institution: 東北大学

    1998 - 1998

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    細胞増殖は増殖因子,サイトカイン等の細胞外刺激によって制御を受けている。Tリンパ球の増殖因子であるインターロイキン2(IL-2)の受容体、γc鎮にはJak3チロシンキナーゼが会合しており、c-myc誘導ならびに細胞増殖に必須の役割を果たしている。我々はJak3ならびにJak2によってチロシンリン酸化される新規分子、STAMがIL-2受容体ならびにGM-CSF受容体からのc-myc誘導や増殖シグナル伝達に関わる機能分子であることをすでに明らかにしている。本研究では、STAMと,STAMに会合し細胞増殖抑制に作用するHgs(Hrs)のinvivo機能解析のために、これらの遺伝子のホモ欠損マウスを作出した。LacZの挿入によりHgsのcoiled-coil構造以下を欠損した形のtargeting vectorを用いて、Hgsノックアウトマウスを作成した。Hgs+/-マウスを交配し得た39匹のF2マウスにHgs-/-マウスが存在しなかったため、E6.5からE14.5のマウス胎仔の解析を行った。Hgs-/-はE10.5以後に認めず、E9.5以前に存在した。Hgs-/-は明らかな形態異常を示し、胎仔初期発生の障害力がみられた。これらの結果からHgsがマウスgastrulationにおいて必須の役割を担って1/)ることが示唆された。一方、STAMホモ欠損マウスは成長遅延と体重減少により、生後16週前後で死亡したが、少なくともin vitroにおけるT細胞の反応性は正常であった。STAMの新規ファミリー分子、STAM2を同定した。STAM2はSTAMとほぼ同等の機能を持つことが分かったことから、STAMホモ欠損マウスではSTAM2によって機能が代償されている可能性が考えられた。

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