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

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.