In vitro and in vivo prevention of human CD8+ CTL-mediated xenocytotoxicity by pig c-FLIP expression in porcine endothelial cells

American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
M TanemuraT Ito

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 comp...Continue Reading

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Citations

Jul 10, 2008·Xenotransplantation·Reto M Baertschiger, Leo H Buhler
Feb 4, 2009·Journal of Cardiovascular Pharmacology·Victoria E A Stoneman, Martin R Bennett
Apr 26, 2012·The Tohoku Journal of Experimental Medicine·Takahiro ItoYutaka Kohgo
Mar 25, 2009·Current Opinion in Organ Transplantation

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