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Tanemura, M. et al.

Tanemura, Saga, Kawamoto, Matsuda-Minehata, Manabe, Deguchi, Nishida, Sawa, Ito,

A Novel Strategy for Preventing Human CD8(+) Cytotoxic T Lymphocyte- Mediated Cytotoxicity Against Pig Endothelial Cells by Overexpression of Pig Cellular FLICE-like Inhibitory Protein (c-FLIP) Gene.

Human CD8(+) cytotoxic T lymphocyte (CTL)-mediated cytotoxicity in xenograft recipients is an important obstacle for successful xenotransplantation of pig organs into humans. In our previous study, we demonstrated that xenocytotoxicity of human CD8(+) CTL detrimental to pig endothelial cells (PEC) is mediated mainly by the Fas/FasL apoptotic pathway. Furthermore, we developed new methods to prevent this CTL killing by extracellular remodeling using overexpression of human decoy Fas antigen and membrane-bound human FasL on pig xenograft cells. The cellular FLICE-inhibitory protein (c-FLIP), a caspase-8 inhibitor that lacks the cysteine domain, is a negative regulator of death receptor-mediated apoptosis. c-FLIP proteins exist as long (c-FLIP(L)) and short (c-FLIPs) splice variants, both capable of protecting cells from death receptor-mediated apoptosis. In this report, we have demonstrated that both pig c-FLIPs and pig c-FLIP(L) significantly inhibit human CD8(+) CTL-mediated xenocytotoxicity toward stably transfected PEC, although the expression level of pig Fas antigen on cell surface was not changed. These data suggested that intracellular remodeling with overexpression of pig c-FLIP in xenograft cells may decrease the innate cellular responses against xenografts, facilitating long-term xenograft survival.[1]

References

A Novel Strategy for Preventing Human CD8(+) Cytotoxic T Lymphocyte-Mediated Cytotoxicity Against Pig Endothelial Cells by Overexpression of Pig Cellular FLICE-like Inhibitory Protein (c-FLIP) Gene. Tanemura, M., Saga, A., Kawamoto, K., Matsuda-Minehata, F., Manabe, N., Deguchi, T., Nishida, T., Sawa, Y., Ito, T. Transplant. Proc. (2006) [Pubmed]

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