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Molecular Mechanisms and Intervention of Immunological Diseases.

Research Project

Project/Area Number 08282101
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionThe University of Tokyo

Principal Investigator

TAKATSU Kiyoshi  Institute of Medical Science, Professor, 医科学研究所, 教授 (10107055)

Co-Investigator(Kenkyū-buntansha) MIYAZONO Kohei  Graduate Sch.Med., University of Tokyo, Professor, 医学系研究科, 教授 (90209908)
NISHIMURA Yasuharu  Graduate Sch.Med., Kumamoto Univ., Professor, 大学院・医学研究科, 教授 (10156119)
MINATO Nagahiro  Graduate Sch.Med., University of Kyoto, Professor, 生命科学研究科, 教授 (40137716)
谷口 維紹  東京大学, 医学系研究科, 教授 (50133616)
笹月 健彦  九州大学, 生体防御研究所, 教授 (50014121)
長田 重一  大阪大学, 医学部, 教授 (70114428)
本庶 佑  京都大学, 医学部, 教授 (80090504)
Project Period (FY) 1996 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥60,100,000 (Direct Cost: ¥60,100,000)
Fiscal Year 2000: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1999: ¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 1998: ¥10,800,000 (Direct Cost: ¥10,800,000)
Fiscal Year 1997: ¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 1996: ¥18,000,000 (Direct Cost: ¥18,000,000)
KeywordsRepertoire selection / Antigen receptor / Immunodiversity / Tyrosine kinase / Inflammation / Immunological disorders / Signal transduction / IL-5 / 免疫職別の多型性 / 免疫職別の多様性 / 免疫制御 / 免疫寛容 / MHCと抗原ペプチド / シグナル伝達 / 抗原レセプター / サイトカイン / 自己免疫病 / アレルギー / 免疫病の分子機構 / 自己認識 / 免疫病 / 免疫不全 / 自己免疫疾患
Research Abstract

Immunological research has been a dual challenge for immunologists and physicians : discovering regulatory mechanism of the complex immune system, and determining how these discoveries may be applied to cure diseases or improve the health mankind. For the last 25 years, tremendous progress has been made in immunological research and clarified components involved in the immune regulation, including genes for antigen receptor and cytokine and its receptor, molecules for MHC gene products and costimulatory signals, and cells in lymphoid and non-lymphoid lineage. Recent advances on embryonic stem cell technology have enabled us to generate numerous numbers of various transgenic and gene-targeted mice. Some of gene-targeted mice provide us a useful tool for evaluating immunological disorders as human models. It is also true that the immune response to endogenous antigen as well as exogenous one trigger the onset of disease such as allergy, autoimmune disease, and severe chronic inflammatory … More disease. More than 10% of total Japanese population suffer from some allergy against environmental allergen such as cedar pollen and house-dust mite. However, it is still remained suffering how we prevent and cure from allergic diseases by immunological maneuver. Many of allergy patients and physicians easily tend to use non-specific inflammatory drugs such as glucocorticoid to treat allergic diseases.
Aims of this research project supported by Grant-in-Aid for core research was to clarify molecular mechanisms and intervention of immunological disorders. We built up four major research groups to accomplish our aims and task each one of which investigated the following project. These are repertoire selection mechanism in early lymphoid development, mechanism of immunological diversity and tolerance and its break-down, mechanism of signaling pathway and its abnormality through antigen and cytokine receptor and costimulatory molecules, and intervention of immunological diseases. For four-year term, a number of exciting results were published in the international journals related in immunology field and in other related fields as well. For example, (1) experimental system to monitor for lymphoid-lineage development from bone marrow stem cells has been established and clarified that B and T cell progenitors are derived from pluripotent stem cells, but not from common lymphoid progenitors. (2) Novel molecules of Toll-like receptor (TLR) family (TLR6 through 11, RP105, and others) and related signaling molecules (MyD88, MD-1, MD-2, and others) were idnetified and their functions were clarified by generating gene knocked-out mice. Results revealed that TLR plays a critical role in protecting host against bacterial infection. (3) Novel signaling molecules coupled with BCR such as BLNK/BASH, with TCR such as pre-TCRα, and with cytokine receptor such as STAM, JAB/SSI-1, CIS, Smad6/7 were cloned and function of each member of molecules were clarified by generating gene-targeting. Intriguing molecular interaction between cytokine signaling molecule and TGF-β receptor signaling molecule was discovered. (4) Role of Btk in human and mouse in B cell development were clarified and mutations of Btk in each of Japanese XLA patients were identified. Role of IL-5 in allergy and mucosal immunology was disclosed and feasibility of anti-IL-5 mAb in preventing allergic asthma was evaluated using allergic guinea pig model. Less

Report

(6 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Yoshida, T., K.Ikuta, S.Takaki, K.Takatsu, et al.: "Defective B-1 cells development and impaired immunity against Angiostrongylus cantonensis in IL-5Rα deficient mice."Immunity. 4. 483-494 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yasue, T., H.Nishizumi, S.Aizawa, K.Takatsu. et al.: "A critical role of Lyn and Fyn for B cell responses to CD38 ligation and interleukin-5."Proc.natl.Acad.Sci.USA.. 94. 10307-10312 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ogata, N., T.Kouro, A.Yamada, K.Takatsu. et al.: "JAK2 and JAK1 are constitutively associate with an interleukin-5 (IL-5) receptor α and βc subunit, respectively, and are activated upon IL-5 stimulation."Blood. 91. 2264-2271 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hiroi, T., M.Yanagida, H.K.Takatsu, H.Kiyono, et al.: "Deficiency of IL-5 receptor α chain selectively influences on the development of IgA producing B-1 cell in mucosa associated tissues."J.Immunol. 162. 821-828 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kinashi, T., T,Asaoka, H.Sagara, K.Takatsu. et al.: "Regulated adhesion by modulating affinity and subcellular localization of integrin VLA-5 (α5β1) in mast cells."J.Immunol. 162. 2850-2857 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mizoguchi, C., S.Uehara, S.Akira, and K.Takatsu.: "Interleukin-5 Induces IgG1 Isotype Switch Recombination in mouse CD38-Activated sIgD-Positive B Lymphocytes."J.Immunol.. 162. 2812-2819 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Katagiri, K., M.Hattori, N.Minato, K.Takatsu, et al.: "Papl is a potent activation signal for LFA-1 distinct from PKC and PI3 kinase."Mol.Cell.Biol. 20. 1956-1969 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Senju, S., K-I.Iyama, H.Kudo, Y.Nishimura, et al.: "Immunocytochemical analyses and targeted disruption of GTPBP1."Mol.Cell.Biol. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukui, Y., o.Hashimoto, T.Sasazuki, et al.: "Highly restricted T cell repertoire shaped by a single major histocompatibility complex-peptide ligand in the presence of a single rearranged T cell receptor beta chain."J.Exp.Med.. 188. 897-907 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsukamoto, N., M.Hattori, N.Minato, et al.: "SPA-1 negatively regulates cell adhesion through GAP activity for Rap 1"J.Biol.Chem.. 274. 18463-18469 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kawamoto, H., T.Ikawa, Y.Katsura, et al.: "T cell progenitors emerge earlier than B cell progenitors in the murine fetal liver."Immunity. 12. 441-450 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Miyazono, K., P.ten Dijke, and C.-H.Heldin: "TGF-β signaling by Smad proteins"Adv.Immunol.. 75. 115-157 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Marine J-C, C.McKay, A.Yoshimura, J.N.Ihle, et al.: "SOCS3 Is essential in the regulation of fetal liver erythropoiesis."Cell. 9. 617-627 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakashima M., K.Sonoda, and T.Watanabe.: "Inhibition of cell growth and induction of apoptotic cell death by a novel human tumor associated antigen, RCAS1"Nature Medicine. 5. 938-942 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kurosaki, T.and S.Tsukada: "BLANK : Connecting Sky and Btk to calcium signals."Immunity. 12. 1-5 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takatsu, K., et al.: "Isolation of phage library clones selected by anti-IL-5 monoclonal antibody"Peptide Sci.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Minato, N., et al.: "Rapl is a potent activation signal for LFA-1 distinct from PKC and PI3-kinase"Mol. Cell. Biol.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nishimura, Y., et al.: "Kira, J-1・HLD-DPB1*0501-associated optico-spinal multiple selerosis : clinical, neuroimaging and immurogenetic studies"Brain. 122. 1689-1696 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Miyazono, K., et al.: "Interaction and functional cooperation of PEBP2/CBF with Smads : synergistic induction of the immunoglobulin germline Cαpromoter."J. Biol. Chem.. 274. 31577-31582 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Miyazono, K., et al.: "C-SKi acts as a transcriptional Co-repressor in TGF-β signaling through interaction with Smads"J. Biol. Chem.. 274. 35269-35278 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takatsu, K., et al.: "Mycobacterium tuberculosisα antigen critical for Vβ11^+Thl cells"Infect. Immun.. Sep, 1 ; 67(9). 4312-4319 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takatsu K..et al.: "JAK1 and JAK2 constitutively associate with an interleukin-5 (IL-5) receptor alpha ans beta subunit,respectively,and are activated upon IL-5 stimulation." Blood. 91(7). 2264-2271 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Minato N.,et al.: "Iron-dependent oxidation,ubiquitination,and degradation of iron regulatory protein 2: implications for degradation of oxidized proteinds." Proc.Natl.Acad.Sci.USA. 95(9). 4924-4928 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishimura Y.,et al.: "Immuno-suppressive peptide for a human T cell clone autoreactive to a unique acetylcholine receptor alpha subunit peptide presented by the disease-susceptible HLA-DQ6 in infant-onset myasthenia gravis." Human Immunol.56. 28-38 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Miyazono K.et al.: "Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase(ASK)1." EMBO J.17(9). 2596-2606 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Taniguchi T.,et al.: "Requirement for IRF-1 in the microenvironment supporting development of natural killer cells." Nature. 391. 700-703 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nagata S.,et al.: "A caspase-activated DNase that degrades DNA during apoptosis,and its inhibitor ICAD." Nature. 391. 43-50 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Watanabe,S.et al.: "JAK2 is essential for activation of c-fos and c-mvc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells." J.Biol.Chem.271. 12681-12686 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Enari,M., et al.: "Sequential activation of ICE-like and CPP-32-like proteases during Fas-mediated apoptosis." Nature. 380. 723-726 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takeda,K.et al.: "Essential role of Stat6 in IL-4 signaling." Nature. 380. 627-630 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamanaka,Y.et al.: "Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation." EMBOJ.15. 1557-1565 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Minegishi,Y.et al.: "Analysis of the CDR3 region of the rearranged IgH chain genes in patients with severe combined immunodeficiency and severe lymphopenia." J.Immunol.156. 4666-4671 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fujihashi,K.et al.: "Interleukin 2(IL-2)and interleukin 7(IL-7)reciprocally induce IL-7 and IL-2 receptors on gamma delta T-cell receptor-positive intraepithelial lymphocytes." Proc.Narl.Acad,Sci.USA. 93. 3613-3618 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yoshida,T.et al.: "Defective B-1 cell development and impaired immunity against Angiostrongylus cantnensis in IL-5Rα-deficient mice" Immunity. 3. 483-494 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Mineta,M et al.: "Contribution of HLA class I and class II alleles to the regulation of antibody production to hepatities B surface antigen in human" Int.Immunol.8. 525-531 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Saitoh,M.et al.: "Identification of important regions in the cytoplasmic juxtamembrane domain of type I receptor that separate signaling pathway of TGF-β" J.Biol.Chem.271. 2769-2775 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nakano,T.et al.: "In vitro development of primitive and definitive erythrocyte from different precursors" Science. 272. 722-724 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Maruo,S.et al.: "IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones" J.Immunol.156. 1748-1775 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Watanabe,S.et al.: "Jak2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells" J.Biol.Chem.271. 12681-12686 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2019-02-15  

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