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Induction of B cell tolerance against Gal-alpha(1-3)Gal Ag in Cyclophosphamide (CP)-induced tolerance

Research Project

Project/Area Number 15390419
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Thoracic surgery
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

TOMITA Yukihiro  KYUSHU UNIVERSITY, Department of cardiovascular surgery, faculty of Medicine, Assistant Professor, 大学病院, 講師 (90180174)

Co-Investigator(Kenkyū-buntansha) YOSHIKAI Yasunobu  Kyusyu University, Department of infection control, Medical Institute of Bioregulation, 生体防御医学研究所, 教授 (90158402)
NISHIDA Takahiro  Kyusyu University, Department of cardiovascular surgery, faculty of Medicine, Research Associate, 大学病院, 助手 (50284500)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2004: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2003: ¥7,800,000 (Direct Cost: ¥7,800,000)
Keywordstolerance / xenotransplantation / natural antibody / alpha-Gal knockout mice / Cyclophosphamide / chimerism / B cell tolerance / heart graft / 薬剤誘導性免疫寛容 / B cell tolernace / clonal destrution / 皮膚移植 / 心移植
Research Abstract

We have previously reported a method of tolerance induction that comprises an i.v. injection of 1x10^8 allogeneic spleen cells (SC) followed, 2 days later, by an i.p. administration of 200mg/kg of CP. By using this method, we were able to induce a long-lasting skin graft (SG) tolerance in H-2 identical combinations. By using alpha-Gal knockout mice which are preimmunized with alpha-Gal Ag and have anti-alpha Gal nAb, we evaluated the effectiveness of this tolerance system to induce B cell tolerance against Gal-alpha(1-3)Gal. <Method> alpha-Gal knockout (alpha-Gal KO ; H-2^<b/d>) and AKR (H-2^k) mice were used as recipients and donors. Group 1 : untreated alpha Gal KO mice. Group 2: alpha-Gal KO mice were injected with 1x10^8 AKR SC on day -2. Group 3 : alpha-Gal KO mice were injected with 1x10^8 AKR SC on day -2 and CP on day 0. The level of anti-alpha-Gal IgM, IgG1, IgG2a, IgG2b, IgG3 was measured by FACS. The kinetics of alpha-Gal nAb-producing Bcells were evaluated with flow cytomet … More ry. AKR heart grafts (HG) were transplanted 2 weeks after the treatments. Histological examination was performed in the transplanted HG. <Result> The production of anti-alpha-Gal IgM and IgG2a was increased two weeks after injection of AKR SC alone. However, the production of anti-alpha-Gal Ab was completely inhibited after treatment with SC and CP during the observation. AKR heart grafts were rejected within 7 days after transplantation in untreated or AKR SC injected alpha-Gal KO mice. Histological analysis showed the hemorrhage within the cardiac muscle and thromboembolism in the coronary artery, i.e., the evidence of humoral rejection. In recipients treated with SC and CP, on the other hand, survival of AKR HG were significantly prolonged and 70% of them survived over 100 days. Histological analysis showed no evidence of humoral rejection. <Conclusion> Our studies confirmed the effectiveness of our cyclophosphamide-induced tolerance system in the induction of humoral tolerance in alpha Gal-knockout mice. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (19 results)

All 2004 Other

All Journal Article (17 results) Publications (2 results)

  • [Journal Article] Role of NKT cells in the suppression of intrathymic effector cells for the establishement of tolerance in cyclophosphamide(CP)-induced tolerance2004

    • Author(s)
      Tomita, Y., T.Iwai, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (Supp.) 78

      Pages: 534-534

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Insignificant role of donor NKT cells in the induction and mainten ance of cyclophosphamide(CP)-induced tolerance2004

    • Author(s)
      Tomita, Y., T.Iwai, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Tranplantation (supp.) 78

      Pages: 534-534

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Generation of NKT-dependent and independent regulatory T cells in cyclophosphamide(CP)-induced tolerance2004

    • Author(s)
      Iwai, T., Y.Toinita, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Tranplantation (supp.) 78

      Pages: 535-535

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of Th1 or Th2 cytokines produced by NKT cells in cyclophosphamide(CP)-induced tolerance2004

    • Author(s)
      Iwai T., Y.Tomita, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Tranplantation (supp.) 78

      Pages: 535-535

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Insignificant role of donor NKT cells in the induction and maintenance of cyclophosphamide(CP)-induced tolerance2004

    • Author(s)
      Tomita, Y., T.Iwai, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (Supp.) 78

      Pages: 534-534

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Generation of NKT-dependent and independent regulatory T cells in cyclophosphamide(CP)-induced tolerance2004

    • Author(s)
      Iwai, T., Y.Tomita, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (Supp.) 78

      Pages: 535-535

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Regulation of Th1 or Th2 cytokines produced by NKT cells in cyclophosphamide(CP)-induced tolerance2004

    • Author(s)
      Iwai T., Y.Tomita, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (Supp.) 78

      Pages: 535-535

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of NKT cells in the suppression of intrathymic effector cells fro the establishment of tolerance in cyclophosphamide (CP)-induced tolerance2004

    • Author(s)
      Tomita, Y., T.Iwai, I.shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (Supp.) 78

      Pages: 534-534

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Insignificant role of donor NKT cells in the induction and maintenance of cyclophosphamide (CP)-induced tolerance2004

    • Author(s)
      Tomita, Y., T.Iwai, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (supp.) 78

      Pages: 534-534

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Generation of NKT-dependent and independent regulatory T cells in cyclophosphamide (CP)-induced tolerance2004

    • Author(s)
      Iwai, T., Y.tomita, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (supp.) 78

      Pages: 535-535

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Regulation of Th1 or Th2 cytokines produced by NKT cells in cyclophosphamide (CP)-induced tolerance2004

    • Author(s)
      Iwai, T., Y.Tomita, I.Shimizu, H.Yasui, et al.
    • Journal Title

      Transplantation (supp.) 78

      Pages: 535-535

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The requirement of higher degree of chimerism for the induction of skin allograft tolerance in cyclophosphamide-induced tolerance

    • Author(s)
      Iwai, T., Y.Tomita, Q-W.Zhang, H.Yasui, et al.
    • Journal Title

      Transplant Int. (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Absent accumulation of Th1 or Th2 cytokines in tolerant heart allografts induced with chimerism-based drug-induced tolerance

    • Author(s)
      Tomita, Y., Q-W.Zhang, G.Matsuzaki, H.Yasui, et al.
    • Journal Title

      Surg Today (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The requirement of higher degree of chimerism for the induction of skin allograft tolerance in cyclophosphamide-induced tolerance

    • Author(s)
      Iwai, T., Y.Tomita, Q-W.Zhang, H.Yasui, et al.
    • Journal Title

      Transplant Int. (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Absent accumulation of Th1 or Th2 cytokines in tolerant heart allografts induced with chimerism-based drug-induced tolerance

    • Author(s)
      Tomita, Y., Q-W.Zhang, G.Matsuzaki, H.Yasui, et al.
    • Journal Title

      Surg Today (In press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The requirement of higher degree of chimerism for the induction of skin allograft tolerance in cyclophosphamide-induced tolerance

    • Author(s)
      Iwai, T., Y.Tomita, Q-W.Zhang, H.Yasui, et al.
    • Journal Title

      Transplant Int. (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Absent accumulation of Th1 or Th2 cytokines in tolerant heart allografts induced with chimerism-based drug-induced tolernace

    • Author(s)
      Tomita, Y., Q-W.Zhang, G.Matsuzaki, H.Yasui, et al.
    • Journal Title

      Surg Today (In press)

    • Related Report
      2004 Annual Research Report
  • [Publications] Iwai, T., Y.Tomita, Q-W.Zhang et al.: "The Requirement of higher degree of chimerism for the induction of skin allograft tolerance in cyclophosphamide-induced tolerance."Transplantat int.. In press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tomita, Y., Q-W.Zhang, I.Shimizu et al.: "Fractionated dosing of cyclophosphamide prevents leucopenic side effects in cyclophosphamide-induced tolerance."Surg.Today. In press. (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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