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The mechanisms of graft failure in cardiac xenografts from α1,3-galactosyltransferase, gene-knockout (GalT-KO) pigs in babooons

Research Project

Project/Area Number 18591787
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionNippon Medical School

Principal Investigator

SHIMIZU Akira  Nippon Medical School, Pathology, Associate professor (00256942)

Co-Investigator(Kenkyū-buntansha) MASUDA Yukinari  Nippon Medical School, Pathology, Instructor (70173755)
ISHIZAKI Masamichi  Nippon Medical School, Pathology, Associate professor (40096954)
SUGISAKI Yuichi  Nippon Medical School, Pathology, Professor (60089620)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,820,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsxenotransplantation / α1,3-galactosyltransferase gene-knockout pig / acute rejection / chronic rejection / humoral rejection / cellular rejection / chronic immunosuppression / baboon / ブタ / ヒヒ
Research Abstract

Heterotopic cardiac xenotransplantation from α1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons has been performed. The pathology of the GalT-K0 cardiac xenografts was assessed to characterize the immunologic reaction to the xenograft in the absence of anti-Gal antibody-mediated rejection.
Eight baboons received heterotopic cardiac xenografts from GalT-KO porcine donors. All baboons were treated with chronic immunosuppression. Histologic and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection occurred. Three baboons were euthanized or died 16 to 56 days after transplantation. The other 5 grafts ceased beating between days 59 and 179 (median 78). All failing grafts exhibited thrombotic microangiopathy (TM) with platelet-rich fibrin thrombi in the microvasculature, myocardial ischemia and necrosis, and focal interstitial hemorrhage. TM developed in parallel with increases in immunoglobulin (IgM and IgG) and complement (C3, C4d, and C5b-9) deposition, as well as with subsequent increases in both TUNEL+ endothelial cell death and endothelial cell procoagulant activation (increased expression of tissue factor and von Willebrand factor, with concomitant decreased expression of CD39). CD3+T cell infiltration occurred in all grafts. Slowly progressive humoral rejection, likely associated with elicited nonGal antibodies, and possibly disordered thromboregulation represents a major remaining immunologic barrier to long-term xenograft survival, even when using GalT-KO swine donors. In addition, acute cellular xenograft rejection and chronic rejection also developed in grafts, maintained by chronic immunosupression.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (15 results)

All 2007 2006 Other

All Journal Article (11 results) (of which Peer Reviewed: 4 results) Presentation (4 results)

  • [Journal Article] GalT-KO pigs:is the cup half empty or half full2007

    • Author(s)
      Sachs DH, Yamada K, Robson SC, Fishman JA, Shimizu A, Colvin RB, Sykes M
    • Journal Title

      Transplantation 84

      Pages: 12-14

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] GalT-KO pigs : is the cup half empty or half full?2007

    • Author(s)
      Sachs, DH., Yamada, K., Robson, SC., Fishman, JA., Shimizu, A., Colvin, RB., Sykes, M
    • Journal Title

      Transplantation 84

      Pages: 12-14

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] GalT-KO pigs: is the cup half empty or half full?2007

    • Author(s)
      Sachs DH, Yamada K, Robson SC, Fishman JA, Shimizu A, Colvin RB, Sykes M
    • Journal Title

      Transplantation 84

      Pages: 12-14

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pathology of renal xenograft rejection in pig to non-human primate transplantation2006

    • Author(s)
      Shimizu A, Yamada K
    • Journal Title

      Clin Transplant (Supple) 15

      Pages: 46-52

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] 超急性拒絶反応:ブタ臓器を用いたヒヒへの異種移植2006

    • Author(s)
      清水 章, 福田 悠, Sachs DH, Yamada K, Colvin RB
    • Journal Title

      日本医科大学医学会雑誌 2

      Pages: 68-69

    • NAID

      130004941866

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Pathology of renal xenograft rejection in pig to non-human primate transplantation.2006

    • Author(s)
      Shimizu, A., Yamada, K
    • Journal Title

      Clin Transplant Supple 15

      Pages: 46-52

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Hyperacute rejection : Pig to baboon xenotransplantation.2006

    • Author(s)
      Shimizu, A., Fukuda, Y., Sachs, DH, Yamada, K., Colvin, RB
    • Journal Title

      Nippon Ikadaigaku Zashi 2

      Pages: 68-69

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Pathology of renal xenograft rejection in pig to non-human primate transplantation2006

    • Author(s)
      Shimizu A, Yamada K
    • Journal Title

      Clin Transplant Supple 15

      Pages: 46-52

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 超急性拒絶反応 : 豚臓器を用いたヒヒへの異種移植2006

    • Author(s)
      清水章, 福田悠, Sachs DH, Yamada K, Colvin RB
    • Journal Title

      日本医科大学医学会雑誌 2

      Pages: 68-69

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Thrombotic microangiopathy associated with humoral rejection incardiac xenografts from a 1,3-galactosyltransferase gene-knockout(GalT-KO)pigs in babooons

    • Author(s)
      Shimizu A, Hisashi Y, Kuwaki K, Tseng Y-L, Dor FJMF, Stuart LH, Robson SC, Schuurman H-J, Cooper DKC, Sachs DH, Yamada K, Colvin RB
    • Journal Title

      Am J Pathol (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Thrombotic microangiopathy associated with humoral rejection in cardiac xenografts from α1,3-galactosyltransferase gene-knockout (GalT-KO) pigs in babooons.

    • Author(s)
      Shimizu, A., Hisashi, Y., Kuwaki, K., Tseng, Y-L., Dor, FJMF, Stuart, LH., Robson, SC., Schuurman, H-J, Cooper, DKC, Sachs, DH., Yamada, K., Colvin, RB
    • Journal Title

      Am J Pathol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 病理学的解析からみたミニブタからヒヒへの臨床応用を目指した異種移植の現状2007

    • Author(s)
      清水 章
    • Organizer
      第17回千駄木感染免疫アレルギー研究会
    • Place of Presentation
      東京
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Xenotransplantation from miniature swine into baboons2007

    • Author(s)
      Shimizu, A
    • Organizer
      17th Sendagi Immunology allergy Conference
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 異種移植における拒絶反応の病理像2006

    • Author(s)
      清水 章
    • Organizer
      第42回日本移植学会総会
    • Place of Presentation
      東京
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] The pathology of rejection in xenotransplantation2006

    • Author(s)
      Shimizu, A
    • Organizer
      42th meeting of Japanese Society of Transplantation
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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