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Analysis of Pathogenic Autoreactive T cells in Patients with Antiphospholipid Syndrome and its Application for Developing Specific Immune Therapies

Research Project

Project/Area Number 12557049
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 内科学一般
Research InstitutionKeio University

Principal Investigator

KUWANA Masataka  Institute for Advanced Medical Research, Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (50245479)

Co-Investigator(Kenkyū-buntansha) KAWAKAMI Yutaka  Institute for Advanced Medical Research, Keio University, School of Medicine, Professor, 医学部, 教授 (50161287)
IKEDA Yasuo  Department of Internal Medicine, Keio University, School of Medicine, Professor, 医学部, 教授 (00110883)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 2002: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥5,400,000 (Direct Cost: ¥5,400,000)
KeywordsAutoantibody / T cell / Thrombosis / Phospholipid / Antiphospholipid antibody / Immuno-therapy / Autoimmune disease / エピトープ / 自己反応性T細胞 / 抗原提示細胞 / 習慣性流産 / T細胞リセプター
Research Abstract

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and intrauterine fetal loss in association with antiphospholipid antibodies. β_2-glycoprotein I (β_2GPI), a plasma glycoprotein that binds various kinds of negatively charged substances including phospholipids, is known to be the most common antigenic target for antiphopholipid antibodies associated with the clinical features of APS. Accumulating evidences in APS patients as well as in experimental APS indicate an important role of β_2GPI-specific CD4^+ T cells in anti-β_2GPI antibody production. In this research project, we have identified and characterized autoreactive CD4^+ T cells to β2GPI that promote antiphospholipid antibody production in APS patients. β_2GPI-specific CD4^+ T cells preferentially recognize the antigenic peptide containing the major phospholipid-binding site in the context of DRB4^*0103 (DR53). T-cell receptor β chains of β_2GPI-specific T cells are highly restricted and mainly utilize rearranged Vβ_7 or Vβ_8 gene segments. T-cell helper activity that stimulates B cells to produce anti-β_2GPI antibodies is mediated through IL-6 and CD40-CD40 ligand engagement. β_2GPI-specific T cells respond to reduced β_2GPI and recombinant β_2GPI fragments produced in bacteria, but not to native β_2GPI, indicating that the epitopes recognized by β_2GPI-specific T cells are apparently cryptic. Activation of β2GPI-specific T cells resulting in production of pathogenic anti-β2GPI antibodies can be induced by the exposure to cryptic peptides of β_2GPI. Finally, β_2GPI-specific T cell is a reasonable target of potential therapeutic strategies that selectively suppress pathogenic antiphospholipid antibody production in APS patients.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Kuwana M, et al.: "Induction of antigen-specific human CD4^+ T cell anergy by peripheral blood DC2 precursors"Eur. J. Immunol. 31. 2547-2557 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al.: "Autoreactive CD4^+ T cell clones to β2-glycoprotein I in patients with antiphospholipid syndrome : preferential recognition of the major phospholipid-binding site"Blood. 98. 1889-1896 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al.: "Restricted T cell receptor β-chain usage by T cells autoreactive to β2-glycoprotein I in patients with antiphospholipid syndrome"Blood. 99. 2499-2504 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al.: "Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura"J. Immunol. 168. 3675-3682 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M: "Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and other dendritic cell subsets"Hum Immunol. 63. 1156-1163 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al.: "Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction : implications for treatment of immune thrombocytopenic purpura"Blood. 101. 621-623 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al: "Induction of antigen-specific human CD^<4+> T cell anergy by peripheral blood DC^2 precursors"Eur. J. Immunol. 31-9. 2547-2557 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al: "Autoreactive CD^<4+> T cell clones to β2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site"Blood. 98-6. 1889-1896 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al: "Restricted T cell receptor β-chain usage by T cells autoreactive to β2-glycoprotein I in patients with antiphospholipid syndrome"Blood. 99-7. 2499-2504 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al: "Spleen is a primary site for activation of platelet-reactive T and B cells in patients with immune thrombocytopenic purpura"J. Immunol. 168-7. 3675-3682 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M.: "Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and other dendritic cell subsets"Hum Immunol. 63-12. 1156-1163 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al: "Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implication for treatment of immune thrombocytopenic purpura"Blood. 101-2. 621-623 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kuwana M, et al.: "Restricted T cell receptor β-chain usage by T cells autoreactive to β2-glycoprotein I in patients with antiphospholipid syndrome"Blood. 99・7. 2499-2504 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 桑名 正隆: "膠原病の病態と自己抗原反応性T細胞"アレルギー・免疫. 9・9. 40-46 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuwana M: "Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and other dendritic cell subsets"Hum Immunol. 63・12. 1156-1163 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuwana M, et al.: "Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction"Blood. 101・2. 621-623 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuwana M: "Autoreactive CD4^+ T cells to β2-glycoprotein I in patients with antiphospholipid syndrome"Autoimmunity Rev. (印刷中).

    • Related Report
      2002 Annual Research Report
  • [Publications] 桑名正隆, 他: "免疫血液疾患研究の進歩と現状:特発性血小板減少性紫斑病"臨床病理. 49・10. 992-995 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kuwana M, et al.: "Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura"Blood. 98・1. 130-139 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Arai T, Kuwana M, et al.: "Autoreactive CD4^+ T cell clones to β2-glycoprotein I in patients with antiphospholipid syndrome"Blood. 98・6. 1889-1896 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 桑名正隆: "T細胞レパートリーの解析"臨床検査. 44・4. 397-404 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 鏑木淳一,桑名正隆: "抗リン脂質抗体症候群の診断と治療"臨床病理. 48・5. 463-468 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kuwana M, et al.: "Analysis of soluble and cell surface factors regulating anti-DNA topoisomerase I autoantibody production demonstrates synergy between Th1 and Th2 autoreactive cells "J Immunol. 164・12. 6138-6146 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kuwana M, et al.: "HLA class II alleles in Japanese patients with immune thrombocytopenic purpura"Tissue Antigens. 56・10. 337-343 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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