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PROLONGED SURVIVAL OF RAT LIVER ALLOGRAFTS TRANSFECTED WITH ADENOVIRUS VECTORS CONTAINNING FAS-LIGAND AND CRM A GENES

Research Project

Project/Area Number 12671171
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General surgery
Research InstitutionNational Children's Medical Research Center

Principal Investigator

LI Xiao-Kang  Dept, of Exper. Sur. & Bioing., National Children's Medical Research Center, Researcher, 小児医療研究センター・実験外科生体工学研究部, 研究員 (60321890)

Co-Investigator(Kenkyū-buntansha) SUZUKI Seiichi  Dept, of Exper. Sur. & Bioing. Natt., National Children's Medical Research Center, Director, 小児医療研究センター・実験外科生体工学研究部, 部長 (00111386)
OKUYAMA Torayuki  Dept, of Exper. Sur. & Bioing., National Children's Medical Research Center, Director, 小児医療研究センター・先天異常研究部, 室長 (40177192)
KIMURA Hiromitsu  Dept, of Exper. Sur. & Bioing., National Children's Medical Research Center, Chief, 小児医療研究センター・実験外科生体工学研究部, 室長 (80115477)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsAdenovirus / Fas-ligand / CrmA / organ transplantation / Cre / loxP / apoptosis / gene therapy / liver / HepG2
Research Abstract

Purpose. Fas-ligand (FasL) plays an important role in immune privileged sites including cornea and testis, to escape from host immune response. Cytokine response modifier A (CrmA), a gene product of cowpox virus, is considered to block Fas/FasL and perforin/granzyme mediated apoptotic pathways in allogeneic transplantation. We investigated in the present study, that FasL and CrmA are the effective genes to prolong survival of rat liver allografts. Methods. FasL and CrmA were expressed in donor liver using adenovirus vector with a Cre-mediated gene delivery system The gene expressions were confirmed by immune staining and their functions were examined with in vitro assay for induction and inhibition of the apoptosis. Using DA (RT-l<a>) to Lewis (RT-l^<l>) rat combination, orthotopic liver transplantation was performed with FasL and/or CrmA gene-transfered grafts. Results. The recombinant adenoviral vectors expressing FasL (AxCALNLFasL) and CrmA (AxCALNLCrmA) under a Cre-mediated switching system were successfully generated and their gene expressions were detected in the transfected cells by immune staining. FasL expressed on the COS-7 cells were induced apoptosis in the Jurkat cell ; CrmA gene-expression dramatically reduced apoptosis in Hep2 cells. The FasL and/or CrmA-transfected DA livers were transplanted into Lewis rats, resulting in a significant prolongation of recipient survival time. Conclusions. Based on these observations, we concluded that an appropriate expression level of FasL in donor liver could act to induce apoptosis to recipient activated T cells, which resulted in the regulation of immune response to the liver allograft. In addition, CrmA is an effective gene-product to prolong recipient survival by the apoptosis modulation activity in the gene-transferred graft.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] X-K.Li, et al.: "Fulminant Hepatitis by Fas-Ligand Expression in MRL-lpr/lpr Mice Grafted with Fas-Positive Livers and Wild-Type Mice with Fas-Mutant Livers"Transplantation. 71. 503-508 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M.Fujino, et al.: "In vitro prevention of cell-mediated xenograft rejection via the Fas/FasL-pathway in CrmA-transducted porcine kidney cells"Xenotransplantation. 8. 115-124 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M.Fujino, et al.: "Selective repopulation of mice liver after fas-resistant hepatocytes transplantation"Cell Transplantation. 10. 353-361 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] X-K.Li, et al.: "アデノウイルスベクターを用いたFasリガンド、CrmA発現によるラット肝移植の生着延長効果"移植. 36(5). 303-315 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] X-K.Li, et al.: "Prolongation of transgene by co-expression of cytokine response modifier A in rodent liver after adenoviral gene transfer"Molecular Therapy. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] L Guo, et al.: "Prolonged survival in rat liver transplantation woth mouse monoclonal antibody against an inducible co-stimulator (ICOS)"Transplantation. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] X-K. Li, M.Fujino, A.Sugioka, M.Morita, T.Okuyama, L.Guo, N.Funeshima, H.Kimura, S.Enosawa, H.Amemiya, and S. Suzuki: "Fulminant Hepatitis by Fas-Ligand Expression in MRL-lpr/lpr Mice Grafted with Fas-Positive Livers and Wild-Type Mice with Fas-Mutant Livers."Transplantation. 71(4). 503-508 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M. Fujino, X-K. Li, T. Suda, M. Hashimoto, K. Okabe, H. Yaginuma, K. Mikoshiba, L. Guo, T. Okuyama, S. Enosawa, H. Amemiya, T. Amano and S. Suzuki: "In vitro prevention of cell-mediated xenograft rejection via the Fas/FasL-pathway in CrmA-transducted porcine kidney cells."Xenotransplantation. 8(2). 115-124 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] M. Fujino, X-K. Li Y. Kitazawa, N. Funeshima, L.Guo, T. Okuyama, T. Amano, H. Amemiya, S.Suzuki.: "Selective repopulation of mice liver after fas-resistant hepatocytes transplantation."Cell Transplantation. 10. 353-361 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] X-K. Li, M. Fujino, K. Adachi, L. Guo, M. Kawasaki, N. Funeshima, Y Kitazawa, M. Hashimoto, T. Okuyama, S. Suzuki: "Prolonged survival of rat liver allografts transfected with adenovirus vectors ontaining Fas-ligand and CrmA genes"Japanese J. of Transplantation. 36(5). 303-315 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] X-K. Li M. Kosuga, K. Tokieda, A. Kanaji, Y. Fukuhara, M. Hashimoto, K. Okabe, H. Yaginuma, M. Yamada, S Suzuki, T. Okuyama.: "Prolongation of transgene by co-expression of cytokine response modifier A in rodenet liver after adenoviral gene transfer."Molecular Therapy. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] L Guo, X-K. Li, N. Funeshima, M. Fujino, Y. Nagata, H.Kimura, H. Amemiya, S. Enosawa, T. Tsuji, Y. Harihhara, M. Makuuchi, S.Suzuki.: "prolonged survival in rat liver transplantation woth mouse monoclonal antibody against an inducible co-stimulator(ICOS)"Transplantation. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] X-K.Li, et al.: "Fulminant Hepatitis by Fas-Ligand Expression in MRL-lpr/lpr Mice Grafted with Fas-Positive Livers and Wild-Type Mice with Fas-Mutant Livers"Transplantation. 71. 503-508 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Fujino, et al.: "In vitro prevention of cell-mediated xenograft rejection via the Fas/FasL-pathway in CrmA-transducted porcine kidney cells"Xenotransplantation. 8. 115-124 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] M.Fujino, et al.: "Selective repopulation of mice liver after fas-resistant hepatocytes transplantation"Cell Transplantation. 10. 353-361 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] X-K.Li, et al.: "アデノウイルスペクターを用いたFasリガンド、CrmA発現によるラット肝移植の生着延長効果"移植. 36(5). 303-315 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] X-K.Li, et al.: "Prolongation of transgene by co-expression of cytokine response modifier A in rodent liver after adenoviral gene transfer"Molecular Therapy. (In press).

    • Related Report
      2001 Annual Research Report
  • [Publications] L Guo, et al.: "Prolonged survival in rat liver transplantation woth mouse monoelonal antibody against an inducible co-stimulator (ICOS)"Transplantation. (In press).

    • Related Report
      2001 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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