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2002 Fiscal Year Final Research Report Summary

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
KeywordsAutoantibody / T cell / Thrombosis / Phospholipid / Antiphospholipid antibody / Immuno-therapy / Autoimmune disease
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.

  • Research Products

    (12 results)

All Other

All Publications (12 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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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

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Published: 2004-04-14  

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