THE IMMUNOMODULATORY EFFECT OF LEFLUNOMIDE IN RAT CARDIAC ALLOTRANSPLANTATION

Leflunomide, a novel immunosuppressant, has been the subject of recent preclinical studies using solid organ allo- and xenotransplantation m odels. The objectives of this study were to evaluate the efficacy and toxicity of leflunomide using a rat cardiac allotransplant model in tw o different strain combinations (DAxPVG and DAxLew). Leflunomide, at d oses ranging between 5 and 30 mg/kg, prolonged graft survival in both strain combinations as effectively as CsA and FK506 1 mg/kg (P < 0.05) . A dose-dependent effect was seen only after a longer treatment cours e, When ongoing rejection was intercepted early (postoperative dag 2), 5 mg/kg was as effective as 1 mg/kg FK506 (P > 0.05) but was inferior to CsA in the DAxPVG combination (P < 0.05), However, in the DAxLew c ombination, leflunomide was equally as efficacious as 15 mg/kg CsA and 1 mg/kg FK506 (P > 0.05). If ongoing rejection was treated at postope rative day 4, 10 mg/kg leflunomide was not only as effective as 15 mg/ kg CsA and 1 mg/kg FK506, but demonstrated a dose-dependent increase i n graft survival in both strain combinations. The toxicity of leflunom ide at doses of especially 5-20 mg/kg was minimal in comparison to the rapeutic doses of CsA and FK506 using body weight and biochemical para meters of renal and liver function. These in vivo observations convinc ingly show leflunomide to be equally as potent an immunosuppressant as CsA and FK506 in transplant rejection, It is also well tolerated on l ong-term administration and, by virtue of this fact, is a potentially suitable candidate for clinical transplantation.