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  • Title: In vitro and in vivo prevention of human CD8+ CTL-mediated xenocytotoxicity by pig c-FLIP expression in porcine endothelial cells.
    Author: Tanemura M, Saga A, Kawamoto K, Deguchi T, Machida T, Nishida T, Sawa Y, Ito T.
    Journal: Am J Transplant; 2008 Feb; 8(2):288-97. PubMed ID: 18211505.
    Abstract:
    Overcoming cell-mediated immunity, especially of human CD8(+) CTLs, is important for the success of xenotransplantation. Our group has previously reported that the cytotoxicity of human CD8(+) CTLs against pig endothelial cells (PEC) is highly detrimental and mediated in major part by the Fas/FasL apoptotic pathway. Cellular FLICE inhibitory protein (c-FLIP) was originally identified as an inhibitor of death-receptor signaling through binding competition with caspase-8 for recruitment to Fas-associated via death domain (FADD). Two major c-FLIP variants result from alternative mRNA splicing: a short, 26-KDa protein (c-FLIP(S)) and a long, 55-KDa form (c-FLIP(L)). The cytoprotective effects of c-FLIP(S/L) in xenograft cells remain controversial. This study demonstrates that the overexpression of c-FLIP(S/L) genes markedly suppress human CD8(+) CTL-mediated xenocytotoxicity and, in addition, the cytoprotective effects of c-FLIP(L) appear to be significantly stronger than those of c-FLIP(S). Furthermore, to prove the prolonged effects of xenograft survival, PEC transfectants with c-FLIP(S/L) genes were transplanted under rat kidney capsules. Prolonged survival was elicited from FLIP(S/L) transfectants, whereas parental PEC was completely rejected through day 5, posttransplant. Thus, intracellular remodeling with the overexpression of c-FLIP(S/L) in xenograft cells may avoid innate cellular attacks against xenografts and facilitate long-term xenograft survival.
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