PROPHYLAXIS OF RENAL ALLOGRAFTS FROM REJECTION BY FTY720 IN CYNOMOLGUS MONKEYS TREATED WITH SUBTHERAPEUTIC DOSES OF CYCLOSPORINE

Abstract

378 Background: The new immunosuppressive drug FTY720 is a modification of a natural compound extracted from the fungus Isaria sinclairii. FTY720 therapy significantly reduces the number of circulating peripheral blood lymphocytes (PBL). The present study examined the in vivo effect of FTY720 in combination with subtherapeutic doses of cyclosporine (CsA) on the survival of kidney allografts in cynomolgus monkeys. Methods: Monkeys transplanted with highly incompatible kidney allografts were treated with daily intramuscular (i.m.) injections of CsA that were adjusted to maintain the blood levels between 40-200 ng/ml. In three experimental groups, recipients received in addition to CsA either 0.1, 0.3, or 1.0 mg/kg/day FTY720 delivered daily by intravenous (i.v.) bolus injections. Results: Recipients treated with CsA alone rejected kidney allografts at a median survival time of 8.5 days (n=4). Recipients that received in addition to subtherapeutic CsA therapy either 0.1 or 0.3 mg/kg/day FTY720 showed significant prolongation of kidney allograft survivals to 71 days (range 36-109 days; n=3; p<0.04) and 63 days (range 10-125 days; n=5; p<0.05), respectively. Transplant biopsy on day 7 in animals treated with 0.1 mg/kg/day FTY720 documented a mild to moderate grade I rejection with focal areas of tubular destruction. Two out of three recipients displayed increased creatinine levels at day 20, and the third recipient at day 41, postgrafting. In contrast, biopsy on day 7 in all five transplants from recipients treated with 0.3 mg/kg/day FTY720 had only a minimal interstitial inflammatory infiltrates without evidence of tubular or arterial damage. Consequently, three out of five recipients in the latter group maintained low creatinine levels up to 45 days postgrafting; in addition, one of these recipients displayed stable kidney function for 125 days. Although recipients treated with CsA and 1.0 mg/kg/day FTY720 had a median of 48 days (range 9-73 days; n=5), two out of five recipients succumbed within 9 and 17 days postgrafting, suggesting possible complications caused by over-immunosuppression. Blood FTY720 through concentrations correlated with significantly decreased levels of PBLs.Conclusions: Addition of FTY720 therapy to a subtherapeutic CsA immunosuppressive regimen effectively blocks the rejection of renal allografts in monkeys.