Immunological evaluation of combination therapy with tacrolimus and sirolimus on long-term allograft survival in nonhuman primates

Abstract

We reported that a 60-day course of combination therapy with tacrolimus and sirolimus induced long-term survival of renal allograft after withdrawal of immunosuppressants in Vervet monkeys. In the present study, the mechanism of drug-induced allograft survival was evaluated via Th1/Th2 cytokines, apoptosis and MLC activity in primates. Materials and methods Cytokines were evaluated by ELISA. MLR and CTL assays were performed by incorporation of 72 hours 3H-TdR and 4 hours 51Cr release assay. Results A 60-day course of tacrolimus with sirolimus resulted in long-term survival of kidney allografts. (67% > 100 days) without intermittent acute rejection. Low sensitivity to MLR was seen in long-term renal allograft survival among monkeys treated with tacrolimus and sirolimus. Increased levels of CD3 +CD8 +, CD3 +/CD56 + NKT cells and CD86 +CD8 −CD11 + dendritic cells were observed. A population of high expression of CD4 +FasL + was detected. In addition, the concentrations of IL-2 and IFN-γ from long-term allograft surviving monkeys was not significantly increased, rather a late phase dominance of Th2, IL-4, IL-10, and TGF-β was found correlated with long-term survival of recipients. In conclusion, the mechanism of tacrolimus and sirolimus induced long-term allograft survival in primates relates to up-regulated FasL expression, NKT cells and dendritic cells, with downregulation of MLR sensitivity. It is also associated with late-dominant expression of Th2 cytokines.