Prolongation of islet allograft survival in mice by combined treatment with pravastatin and low-dose cyclosporine

Pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in hibitor, is known to have suppressive effects on immune and inflammatory ce lls. We have previously shown in mice and dogs that this agent prevents pri mary nonfunction of islet iso- and autografts by reducing inflammation at t he graft site. The present study was designed to further investigate whethe r pravastatin has a synergistic effect with cyclosporine (Cs) to prolong is let allograft survival in mice. Unpurified 3000 BALB/c newborn islets were transplanted under the renal capsule of a streptozotocin-diabetic C57BL/6 m ouse. Pravastatin and Cs were administered for 10 days starting on the day of grafting (day 0). Five groups were set up based on the treatment protoco l: group 1, treatment with 40 mg/kg pravastatin; group 2, 30 mg/kg Cs; grou p 3, 50 mg/kg Cs; group 4, 40 mg/kg pravastatin and 30 mg/kg Cs; group 5, v ehicle alone. Graft survival was indicated by blood glucose levels sustaine d at < 200 mg/dl, and graft rejection by > 250 mg/dl for 2 consecutive days . Hyperglycemia persisted in six of the eight (75%) mice and grafts were re jected in 3.6 +/- 0.5 days (mean +/- SD) in group 5. In group 1, grafts wer e also rejected in 3.8 +/- 0.8 days, but blood glucose was transiently < 20 0 mg/dl in three of the five mice. Despite Cs, grafts were rejected between 7 and 15 days (10.3 +/- 2.4 days) in group 2. Among six mice in group 3, o ne maintained euglycemia for > 60 days, the other rejected the a raft on da y 15, and the remaining four died with functioning grafts between 9 and 13 days due to Cs toxicity. A combination of a low dose of Cs and pravastatin (group 4) prolonged graft survival for > 19 days in five of the eight mice, and for 7-13 days in the remaining three mice. Histological examination of the grafts in this group showed significantly reduced local inflammation. Results indicate a synergistic effect of pravastatin and Cs on prevention o f islet allograft rejection.