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The authors' previous study has shown that liposome-mediated ex vivo intracoronary interleukin (IL)-4 and IL-10 combined gene therapy suppressed the allo-immune responses and prolonged the cardiac allograft survival by 15 folds. However, the mechanism for promoting long-term allograft survival remains unknown.This study tested the hypothesis that this combined cytokine gene targeting may promote alloreactive T-cell apoptosis or prevent apoptosis of cardiac allograft myocytes through Fas/Fas ligand (FasL) pathway. A rabbit functional cervical heterotopic heart transplantation model was used, and plasmid human recombinant IL-4 and IL-10 gene complexed with cationic liposome (GAP/DLRIE) was delivered into cardiac allografts by intracoronary infusion ex vivo.This liposome-mediated IL-4 and IL-10 combined gene therapy significantly increased apoptotic T cells detected by TUNEL staining. The caspase-8 or caspase-3 expressing T cells were also significantly increased. The Fas+ apoptotic T cells dominated in the population of apoptotic CD4+ T cells, but FasL+ CD4+ T-cell population was less effected in the combined gene therapy group. The effect of combined gene therapy on the infiltrative Fas+ CD8+ T-cell population is much less than that on Fas+ CD4+ cells, and there was almost no effect on the FasL+ CD8+ T-cell population. Furthermore, localized IL-4 and IL-10 combined gene therapy protected cardiac allograft myocytes by down-regulating its FasL expression, but not Fas.These results suggest that this combined gene targeting strategy which induced localized overexpression of exogenous IL-4 and IL-10 may promote alloreactive T-cell apoptosis and prevent myocytes apoptosis through Fas/FasL cell surface interaction, therefore inducing cardiac allograft tolerance.