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Adhesion molecules and soluble factors specifically regulate T lymphocyte function in patients with rheumatoid arthritis.

Research Project

Project/Area Number 05670438
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 内科学一般
Research InstitutionUniversity of Occupational & Environmental Health (U.O.E.H.)

Principal Investigator

TANAKA Yoshiya  U.O.E.H., Medicine, Instructor, 医学部, 助手 (30248562)

Co-Investigator(Kenkyū-buntansha) SHIRAKAWA Fumihiko  U.O.E.H., Medicine, Assist.Prof., 医学部, 講師 (10158967)
OTA Toshiyuki  U.O.E.H., Medicine, Assoc.Prof, 医学部, 助教授 (10140930)
ETO Sumiya  U.O.E.H., Medicine, Professor, 医学部, 教授 (90010347)
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1993: ¥900,000 (Direct Cost: ¥900,000)
Keywordsrheumatoid arthritis / T lymphocyte / endothelium / adhesion molecules / integrin / proteoglycan / MIP-1beta / IL-1 / T細胞 / 滑膜細胞 / サイトカイン / ケモカイン
Research Abstract

Synovitis in rheumatoid arthritis (RA) is characterized by infiltration of synovium by T cells as well as the proliferation of synovial lining cells. We have studied the mechanism of circulating T cell migration into synovial tissue and interaction of T cells with synovial cells from the standpoints of adhesion molecules, cytokines and proteoglycan.
1.The mechanisms of T cell infiltration into rheumatoid synovium.
We have studied the mechanism of T cell adhesion to endothelium and have proposed that it consists of inflammatory adhesion cascade. To clarify the mechanism of T cell migration into synovial tissue, we assessed the adhesion of peripheral T cells to endothelial cells purified from rheumatoid synovium. The endothelial cells expressed heparan sulfate proteoglycan as well as adhesion molecules such as ICAM-1, VCAM-1 and E-selectin. T cells in synovium produced large amounts of inflammatory cytokine MIP-1beta. The MIP-1beta was most effective when immobilized on the heparan sulfate … More expressed on the rheumatoid endothelium to trigger T cell integrin which lead to the induction of high affinity adhesion of T cells to the endothelium. We reasoned that, as cytokines in vivo will be rapidly washed away by blood flow, MIP-1beta can induce T cell adhesion in its immobilized form. The induced T cell adhesion was inhibited by either, the mixture of anti-VLA-4/LFA-1 antibodies, xyloside which inhibits the synthesis of heparan sulfate, or pertussis toxin which blocks signal transduction through G-protein coupled MIP-1beta receptor. These results indicate that MIP-1beta produced from synovial T cells induces integrin-mediated T cell adhesion to endothelium by its immobilized form on heparan sulfate on synovial endothelium. Thus, cytokines and proteoglycan as well as adhesion molecules are involved in T cell migration into synovium, which leads to accumulation of T cells in rheumatoid synovium. Extrapolation to include the results would bring new approaches to clarification of pathogenesis and pharmacological agents in RA.
2.The mechanisms of cellular interaetion of T cells with synovial cells
Synovial lining cells and T cells play a central role in rheumatoid synovitis. We studied the interaction between T cells and synovial fibroblasts. T cells adhered to the synovial cells mainly through LFA-1/ICAM-1. Histochemical studies indicated that LFA-1-positive T cells accumulated around ICAM-1-positive synovial cells. We found that T cells activated synovial cells to induce IL-1beta production through the cellular adhesion via LFA-1/ICAM-1. To clarify if ICAM-1 per se on the synovial cells induce activation signals, ICAM-1 on a synovial fibroblast cell line established rocally was cross-linked and IL-1beta production was assessed. Cross-linked ICAM-1 induced transcription of IL-1beta genomic DNA through enhancer regions containing nuclear factor AP-1-binding sites by CAT analysis. The involvement of AP-1 in ICAM-1-induced IL-1beta transcription was confirmed by bandshift assay. These results indicate that adhesion molecules not only function as glue but transduce activation signals which induce cytokine production through nuclear factor in rheumatoid synovial cells. Thus, the significance of T cell adhesion to synovial cells by LFA-1/ICAM-1 pathway in the pathogenesis of synovitis is suggested, which may bring new approaches to the control of synovitis. Less

Report

(3 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Yoshiya Tanaka: "T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1β" Nature. 361. 79-82 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yoshiya Tanaka: "Proteoglycan on endothelial cell present adhesion-inducing cytokines to leukocytes" Immunology Today. 14. 111-115 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamas Schweighoffer: "Selective expression of integrin α4β7 on a subset of human CD4+ memory T cells with hallmarks of gut-trophism" Journal of Immunology. 151. 717-729 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] David A.Adams: "Hepatocyte growth factor and macrophage inflammatory protein-1β:structurally distince cytokines that induce rapid cytoskeletal changes and subset-preferantial migration of T cells" Proc.Natl.Acad.Sci.USA. 92. 7144-7148 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 田中 良哉: "T細胞接着カスケード:接着分子・接着誘導分子・サイトカイン・プロテオグリカンの作用機構" 日本臨床免疫学会雑誌. 16. 486-491 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 田中 良哉: "RAにおける接着分子の過剰発現とその制御の可能性" 臨床免疫. 26. 190-197 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yoshiya Tanaka: "Regulation of leukocyte recruitment by proadhesive cytokines immobilized on endothelial proteoglycan In Adhesion in leukocyte homing and differentiation" Springer-Verlag,Berlin, 10 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yoji Shimizu: "Integrins and homing receptors in autoimmunity In the molecular pathology of autoimmunity" Harwood Academic Puiblishers,New York, 10 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, Y., Albelda, S.M., Horgan, K.J., van Seventer, G.A., Shimizu, Y., Newman, W., Hallam, J., Newman, P.J., Buck, C.A., Shaw, S.: "CD31 expressed on distinctive T cell subsets is a preferential amplifier of beta1 integrin-mediated adhesion." J.Exp.Med.176. 245-253 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Shimizu, Y., Newman, W., Tanaka, Y., Shaw, S.: "Lymphocyte interactions with endothelial cells." Immunol.Today. 13. 106-112 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Horgan, K., J., Tanaka, Y., Shaw, S.: "Post-thymic differentiation CD4 T lymphocytes : Naive versus memory subsets and further specialization among memory cells." Prog.Chem.Immunol.54. 72-102 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, Y., Adams, D.H., Hubscher, S., Hirano, H., Siebenlist, U., Shaw, S.: "T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1beta." Nature. 361. 79-82 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, Y., Adams, D.H., Shaw, S.: "Proteoglycans on endothelial cells present adhesion-inducing cytokines to leukocytes." Immunol.Today. 14. 111-115 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, Y., Adams, D.H., Shaw, S.: "Regulation of leukocyte recruitment by proadhesive cytokines immobilized on endothelial proteoglycan." In Adhesion in leukocyte homing and differentiation. Dunon, D., Mackay, C.R., Imhof, B.A., editors. Springer-Verlag, Berlin.99-108 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, Y., Shaw, S.: "T cell adhesion cascades : general considerations and illustrations with CD31." In Mechanisms of lymphocyte activation and immune regulation IV.Gupta, S., Waldmann, T.A., editors. Plenum Press, New York.157-161 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Shimizu, Y., Tanaka, Y., & Shaw, S.: "T cell adhesion molecules : relevance to autoimmunity." In The Molecular Pathology of Autoimmunity. Bona, C.A., Siminovitch, K., Theofilopoulos, A.N., Zanetti, M., editors. Harwood Academic Publishers, New York.169-178 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Schweighoffer, T., Tanaka, Y., Tidswell, M., Erle, D.J., Horgan, K.J., Ginther Luce, G.E., Lazarovits, A.I., Buck, D., Shaw, S.: "Selective expression of integrin alpha4beta7 on a subset of human CD4+ memory T cells with hallmarks of gut-trophism." J.Immunol.151. 717-729 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, Y.: "T cell adhesion cascade : the involvement of adhesion molecules, adhesion-inducing molecules.cytokines and proteoglycans." Jpn.J.Clin.Immunol.16. 486-491 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, Y.: "Adhesion molecules in rheumatoid arthritis : mechanisms and new approaches to the therapy." Clin.Immunol.26. 190-197 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Adams, D.A., Harvath, L., Bottaro, D.P., Interrante, R., Catalano, G., Tanaka, Y., Strain.A., Hubscher, S.G., Shaw, S.: "Hepatocyte growth factor and macrophage inflammatory protein 1beta : structurally distinct cytokines that induce rapid cytoskeletal changes and subset-preferential migration of T cells." Proc.Natl.Acad.Sci.USA. 92. 7144-7148 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 田中良哉: "T細胞接着カスケード:接着分子・接着誘導分子・サイトカイン・プロテオグリカンの作用機構" 日本臨床免疫学会雑誌. 16. 486-491 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] 田中良哉: "RAにおける接着分子の過剰発現とその制御の可能性" 臨床免疫. 26. 190-197 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 田中良哉: "接着分子と炎症-接着分子とサイトカインの接点" 感染・炎症・免疫. 24. 158-165 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 田中良哉: "炎症部への遊出-接着分子とサイトカインの接点" 臨床免疫. 24. 832-840 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 田中良哉: "接着分子と臨床" 医学のあゆみ. 168. 174-176 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yoshiya Tanaka: "Proteoglycan on endothelial cell present adhesion-inducing cytokines to leukocytes" Immunlogy Today. 14. 111-115 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yoshiya Tanaka: "Regulation of leukocyte recruitment by proadhesive cytokines immobilized on endothelial proteoglycan In Adhesion in leukocyte homing and differentiation" Springer-Verlag,Berlin, 10 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yoji Shimizu: "Integrins and homing receptors in autoimmunity In the molecular pathology of autoimmunity" Harwood Academic Puiblishers,New York, 10 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] 田中良哉: "RAにおける接着分子の過剰発現とその制御の可能性" 臨床免疫. 26. 190-197 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 田中良哉: "慢性関節リウマチとサイトカイン" Mebio. 11. 24-32 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 田中良哉: "接着分子と臨床" 医学のあゆみ. 168. 174-176 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 田中良哉: "T細胞接着カスケード:接着分子・接着誘導分子・サイトカイン・プロテオグリカンの作用機構" 日本臨床免疫学会雑誌. 16. 486-491 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Schweighoffer,T.: "Selective expression of integrin alpha_Abeta_7 on a subset of human CD4+ memory T cells with hallmarks of gut-trophism" Journal of lmmunology. 151. 717-729 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Tanaka,Y.: "T-cell adhesion induced by proteoglycan-immobilized cytokine" Nature. 361. 79-82 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] 田中良哉: "抗サイトカイン療法.慢性関節リウマチ治療の新たなアプローチ" 先端医学社(印刷中), (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Tanaka,Y.: "Regulation of leukocyte recruitment by proadhesive cytokines immobilized on endothelial proteoglycan In Adhesion in leukocyte homing and differentiation" Springer-Verlag,Berlin, 260 (1993)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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