Prolongation of heterotopic cardiac allografts in rats by cyclosporin A.

Abstract

Cyclosporin A (CsA), an investigational immunosuppressive drug, was tested for its ability to prevent rejection of heterotopic rat heart allografts transplanted across a major histocompatibility barrier (ACI to Lewis). The relative efficacy of CsA was compared to a combination of azathioprine and prednisolone. Various dose-schedule combinations of CsA as a single drug were evaluated in regard to duration of grafts beating, recipient mortality rate, and histology of long-term functioning grafts. A daily dose of CsA of 10 mg/kg prevented rejection, but was associated with a 40% recipient mortality rate from infection. CsA in 5 mg/kg/day doses resulted in long-term graft function (> 100 days), but histological examination of these grafts showed mild rejection. A dose-schedule of CsA in 10 mg/kg/day for 7 to 35 days followed by a reduction to 5 mg/kg/day prolonged the survival rate of all grafts to longer than 100 days; no rats died from this treatment and there was no evidence of rejection on graft histology. In contrast, a combination of 4 mg/kg/day azathioprine and 4 mg/kg/day prednisolone did not prolong graft survival rates. Azathioprine in 30 mg/kg and prednisolone in 12 mg/kg prolonged allograft survival (50 to 60 days), but was associated with significant recipient morbidity (> 25% weight loss) and histological evidence of acute and chronic rejection. A nontoxic dose of CsA is superior to a combination of azathioprine and prednisolone in preventing the rejection of heterotopic rat heart allografts. The therapeutic index of cyclosporin A in rats can be increased by using a tapering dose schedule, as opposed to a fixed dose schedule. CsA has good potential for clinical application to organ transplantation.