A short-term combination therapy with cyclosporine and rapamycin or leflunomide induces long-term heart allograft survival in a strongly immunogenic strain combination in rats

Abstract  Synergism between cyclosporine (CsA) and rapamycin (RAPA) or leflunomide (LF) was studied in a strongly immunogenic cardiac allograft model in rats. In the absence of immunosuppression, PVG recipients rejected WKAH heart grafts after a mean survival time (MST) of 5.2 ± 1.1 days. A dose of 7.5 mg/kg per day CsA did not prolong graft survival (MST 5.6 ± 1.2 days). CsA given at 10 mg/ kg per day for 30 days extended MST of the grafts to 48 ± 7 days. A short course of combination therapy consisting of adding a non-therapeutic dose of RAPA or a subthera-peutic dose of LF to a 1-month course of CsA resulted in permanent graft survival. These data suggest that RAPA and LF synergize with CsA enabling not only the lowering of the dose of CsA, but also inducing transplantation tolerance.