Prolongation of rat islet allograft survival by the immunosuppressive agent leflunomide

The purpose of this study was to investigate the effect of Leflunomide (Lef), alone or in combination with a suboptimal dose of cyclosporine (CsA), on rat allogeneic islet transplantation. Two thousands islets were transplanted under the left kidney capsule of a streptozocin-induced diabetic Lewis recipient. In the ACI to Lewis combination, the mean survival time (MST) of the untreated group was 5.2 +/- 0.8 days. Lef at 2.5, 5, and 10 mg/kg/day for 14 days significantly prolonged MSTs to 19.0 +/- 1.6, 29.8 +/- 3.7, and 29.0 +/- 5.3 days (P<0.01), respectively. CsA at 5 mg/kg/day also prolonged graft survival to 21 +/- 3.5 days. When CsA (5 mg/ kg/day) was combined with Lef (5 or 10 mg/kg/day) and administered for 14 days, the survival rate of the islet allografts was further increased to 34.8 -/+ 4.7 and 36.0 -/+ 6.6 days, respectively. When Lef or CsA monotherapy was extended to 28 days at a dose of 5 mg/kg/ day, MSTs were further increased to 45.8 -/+ 8.8 or 37.4 -/+ 4.7 days, respectively. Graft MST was 56.4 -/+ 9.9 days when Lef and CsA combination therapy was administered for 28 days. In the Brown-Norway to Lewis combination, MST of the allogeneic islets in untreated rats was 6.2 -/+ 0.8 days. When Lef or CsA alone, at 5 mg/kg/day, was administered for 28 days, two of seven Lef-treated rats remained normoglycemia for more than 100 days. Graft survival longer than 100 days occurred in one of five CsA-treated rats, and in five of eight rats treated with the combination of Lef and CsA. The graft-bearing left kidney was removed after 100 days in rats with functional islet allografts, and a second Brown-Norway islet graft was transplanted into the right kidney. In all recipients, the second graft was rejected by 9.8 -/+ 1.5 days. In summary, our findings demonstrate that Lef prolonged allogeneic islet graft survival, and its immunosuppressive effect was improved when combined with CsA.