THE EFFECTS OF LEFLUNOMIDE AND CYCLOSPORINE-A ON REJECTION OF CARDIACALLOGRAFTS IN THE RAT

Leflunomide is a new low molecular weight immunosuppressive drug which inhibits the enzymes dehydroorotate-dehydrogenase and protein tyrosin e kinase, both of which are important components in the immune respons e. As the mechanisms of action of leflunomide and cyclosporin A (CsA) are different, we postulated a synergistic effect of the two drugs and tested graft survival following leflunomide administration alone or i n combination with CsA in a rat cardiac transplantation model. Low-and high-responder rat strain combinations were used in parallel and the experiments were performed both with and without challenge with Linomi de, an immunomodulator which promotes graft rejection in this model. I n the low-responder rat strain combination (Piebald Virol Glare graft to Dark Agouti recipient; PVG to DA), graft survival appeared to be a dichotomous variable, being characterized by tolerance or early reject ion. Leflunomide (10 or 5 mg/kg) given for 10 days induced tolerance a nd CsA did Likewise; the addition of Linomide abolished the immunosupp ressive effect of leflunomide but not that of CsA. In the high-respond er combination (DA to PVG), no tolerance was seen and graft survival w as moderately prolonged both after leflunomide and after CsA treatment , the addition of Linomide to CsA or to leflunomide (5 mg/kg) abolishe d the immunosuppressive effect of the drugs. However, when CsA-Linomid e or leflunomide-Linomide were supplemented with the second immmunosup pressive drug leflunomide or CsA respectively, graft survival was sign ificantly prolonged (P < 0.001 in both cases). This suggests leflunomi de and CsA have additive potential.