2001 Fiscal Year Final Research Report Summary
PROLONGED SURVIVAL OF RAT LIVER ALLOGRAFTS TRANSFECTED WITH ADENOVIRUS VECTORS CONTAINNING FAS-LIGAND AND CRM A GENES
| Project/Area Number |
12671171
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | National Children's Medical Research Center |
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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)
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| 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)
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| Project Period (FY) |
2000 – 2001
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| Keywords | Adenovirus / Fas-ligand / CrmA / organ transplantation / Cre / loxP / apoptosis / gene therapy / liver |
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| 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.
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Research Products
(12 results)
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[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)
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「研究成果報告書概要(欧文)」より
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[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)
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「研究成果報告書概要(欧文)」より
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[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).
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「研究成果報告書概要(欧文)」より
