IN-VIVO EFFECTS OF LEFLUNOMIDE ON NORMAL PANCREATIC-ISLET AND SYNGENEIC ISLET GRAFT FUNCTION

Leflunomide (Lef) is a novel immunosuppressant that can prevent islet allograft and xenograft rejection, In this study, we investigated the in vivo effects of Lef on the function of normal pancreatic islets and syngeneic islet grafts in rats and compared its effect to cyclosporin e (CsA) and FK506. Different groups of rats were treated with Lef (10 and 20 mg/kg/day), CsA (20 mg/kg/day), or FK506 (2 mg/kg/day), After 4 and 6 weeks, nonfasting blood glucose (BG) levels of all the treatmen t groups were not different from that of the control group, Intravenou s glucose tolerance test revealed that the rate of glucose disappearan ce was normal in Lef-treated groups, However, the rate of glucose disa ppearance in the CsA- and FK506-treated rats was impaired, In contrast , long-term (7 months) treatment of rats with CsA (10 mg/kg/day) resul ted in five of seven rats developing hyperglycemia. However, normal BG was observed in all rats treated for 7 months with Lef (10 mg/kg/day) , In the second experimental model, streptozocin-induced diabetic ACI rats were grafted with an average of 1200 syngeneic islets into the li ver or kidney capsule, Diabetes in these ACI recipients was stably rev ersed for 6 months, then these rats were treated with Lef (20 mg/kg/da y), CsA (20 mg/kg/day), and FK506 (2 mg/kg/day), After 14 days of trea tment, nonfasting BG levels were significantly increased in rats treat ed with CsA (before: 105+/-2.9 mg/dl, after: 275.8+/-60 mg/dl) as well as in rats treated with FK506 (before: 108+/-2.4 mg/dl, after: 209+/- 10.1 mg/dl). In contrast, the BG levels of the Lef-treated rats were i ndistinguishable from those of the untreated control groups. Site of t ransplantation, i.e., liver and kidney, did not affect the results, Ou r results indicating that Lef has no diabetogenic property in vivo len ds support to the promise that leflunomide may be effective for clinic al islet transplantation.