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Development of a new cell therapy by adoptive transfer of regulatory T cells to induce immunological tolerance for the transplanted liver

Research Project

Project/Area Number 14570455
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionNIIGATA UNIVERSITY

Principal Investigator

ICHIDA Takafumi  NIIGATA UNIVERSITY, Medical and Dental Hospital, Associate Professor, 医歯学総合病院, 助教授 (00126509)

Co-Investigator(Kenkyū-buntansha) YAMAGIWA Satoshi  NIIGATA UNIVERSITY, Medical and Dental Hospital, Clinical Staff, 医歯学総合病院, 医員 (10419327)
WATANABE Hisami  University of the Ryukyu, Center of Molecular Biosciences, Professor, 遺伝子実験センター, 教授 (50143756)
MATSUDA Yasunobu  NIIGATA UNIVERSITY, Medical and Dental Hospital, Assistant, 医歯学総合病院, 助手 (40334669)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsRegulatory T cells / Immunological tolerance / Liver transplantation / Cell therapy
Research Abstract

(1)Generation of human regulatory CD4^+CD25^+ T cells
We confirmed that naive CD4^+ cells stimulated with alloantigens in the presence of TGF-β(transforming growth factor-β) differentiate into suppressor cells with a phenotype and functional properties similar if not identical with natural regulatory CD4^+CD25^+ T cells. We also studied the regulatory properties of other cytokines, separately or together with TGF-β, on CD4^+CD25^+ T cells generated by allo-stimulation. Although it has been reported that CD4^+ cells become regulatory T cells ('Tr1 cells') when repeatedly stimulated with IL-10,IL-10 inhibited CD25 expression on CD4^+* cells. Moreover, when naive CD4^+ cells were stimulated with alloantigens in the presence of both IL-10 and TGF-β,IL-10 inhibited the effect of TGF-β on the generation of CD4^+CD25^+ T cells.
(2)Generation of murine regulatory CD4^+CD25^+ T cells
We found that treatment of murine alio-activated CD4^+ T cells with TGF-β and IL-2 also enhanced expression of CD25 and enabled these cells to develop potent suppressive activity. We are planning to use those CD4^+CD25^+ T cells generated ex vivo in skin transplantation model to examine whether transfer of those cells can prevent graft rejection.
(3)CD4^+CD25^+ T cells in the human liver
We also investigated CD4^+CD25^+ T cells in human livers. Although the proportion of CD4^+CD25^+ T cells in the liver was lower than in the peripheral blood, we found a significant increase of CD4^+CD25^+ T cells in the marginal regions of hepatocellular carcinoma(HCC), but not in unaffected areas of the liver. CD4^+CD25^+ T cells isolated from peri-tumor regions of HCC displayed phenotype markers characteristic of regulatory T cells, and inhibited autologous CD8^+ cell proliferation. Our results suggest that CD4^+*CD25^+ T cells in the peri-tumor region of HCC inhibit the generation of tumor-specific CD8^+ cytotoxic T cell activity and, thereby, contribute to the progression of HCC.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] 市田 隆文 他1名: "免疫抑制剤"医薬ジャーナル増刊号. 40(S-1). 386-389 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato Y, et al.: "Repeated intraportal donor specific transfusion may induce tolerance following adult living related donor liver transplantation."Hepatogastroenterology. 50. 601-606 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato Y, et al.: "Analysis of microchimerism in peripheral blood by short tandem repeated sequences immediately after living related liver transplantation."Transplantation Proceedings. 35(1). 412-413 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 楊 秀華, 他8名: "肝細包癌周囲非癌部に増加するCD4陽性CD25陽性T細胞の解析"消化器と免疫. 39. 124-126 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uehara K, et al.: "Systemic administration of liposome-encapsulated OK-432 prolongs the survival of rats with hepatocellular carcinoma through the induction of IFN-γ-producing hepatic lymphocytes."Journal of Gastroenterology and Hepatology. 17(1). 81-90 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sugahara S, et al.: "Thymosin-alphal increases intrahepatic NKT cells and CTLs in patients with chronic hepatitis B."Hepatology Research. 24(4). 346-354 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ichida T, et al.: "Immunosuppressants."lyaku journal. 40(S-1). 286-289 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato Y, et al.: "Repeated intraportal donor specific transfusion may induce tolerance following adult living related donor liver transplantation."Hepato-Gastroenterol. 50. 601-606 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato Y, et al.: "Analysis of microchimerism in peripheral blood by short tandem repeated sequences immediately after living related liver transplantation."Transplantation Proc.. 35(1). 412-413 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yang XH, et al.: "Analysis of CD4+CD25+ T cells accumulating marginal regions of hepatocellular carcinoma."Digestive Organ and Mucosal Immunology. 39. 124-126 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Uehara K, et al.: "Systemic administration of liposome-encapsulated OK-432 prolongs the survival of rats with hepatocellular carcinoma through the induction of IFN-γ-producing hepatic lymphocytes."J.Gastroenterol.Hepatol.. 17(1). 81-90 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sugahara S, et al.: "Thymosin-alphal increases intrahepatic NKT cells and CTLs in patients with chronic hepatitis B."Hepatol.Research. 24(4). 346-354 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sato Y, et al.: "Repeated intraportal donor specific transfusion may induce tolerance following adult living related donor liver transplantation"Hepatogastroenterology. 50. 601-606 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 市田 隆文他1名: "免疫抑制剤"医薬ジャーナル増刊号. 40(S-1). 386-389 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sato Y, et al.: "Analysis of microchimerism in peripheral blood by short tandem repeated sequences immediately after living related liver transplantation"Transplantation Proceedings. 35(1). 412-413 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sato Y, et al.: "Shear stress theory and small-for-size graft in adult living related liver transplantation"Transplantation Proceedings. 35(1). 78 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto S, et al.: "A successful treatment of positive cross-match by treatment with postoperative repeated donor whole blood administration via portal vein in adult, living related partial liver transplantation : a case report"Transplantation Proceedings. 35(1). 383-384 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Oya H, et al.: "Changes in serum cytokine levels and donor-specific transfusion via portal vein during the early period following living related donor liver transplantation"Transplantation Proceedings. 35(1). 409 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Uehara K, et al.: "Systemic administration of liposome-encapsulated OK-432 Prolongs the survival of rats with hepatocellular carcinoma through the induction of IFN-γ-producing hepatic lymphocytes"J. Gastroenterol. Hepatol.. 17(1). 81-90 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 楊 秀華, 他8名: "肝細胞癌周囲非癌部に増加するCD4陽性CD25陽性T細胞の解析"消化器と免疫. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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