INHIBITION OF SMOOTH-MUSCLE CELL-PROLIFERATION IN-VITRO BY LEFLUNOMIDE, A NEW IMMUNOSUPPRESSANT, IS ANTAGONIZED BY URIDINE

Chronic rejection in the form of graft vascular disease (GVD) continue s to plague clinical transplantation of vascularized organs. The histo pathology of this lesion is characterized by neointimal hyperplasia, s mooth muscle cell proliferation, and obliterative arteriopathy. Due to the lack of effective medical therapy for preventing or reversing the se chronic vascular changes, retransplantation remains the final resor t in treatment. Some of the newer immunosuppressive agents, including the new isoxazole derivative leflunomide (LFM), have shown efficacy in preventing chronic rejection in animal models of transplantation. Alt hough its mechanism of action remains incompletely elucidated, previou s work using lymphocytes in vitro suggests that the drug might act as a tyrosine kinase inhibitor, an inhibitor of de novo pyrimidine biosyn thesis, or both. In order to elucidate whether the efficacy of LFM in vivo is attributable not only to anti-proliferative effects on the rec ipient immune system but also to direct effects on mesenchymal cells i n the donor organ, we examined the effects of LFM on a transformed 9E1 1G murine smooth muscle cell (M-SMC) line in vitro, We demonstrate her e that the active metabolite of LFM, A77 1726, dose-dependently inhibi ts the constitutive and growth-factor stimulated proliferation of M-SM C in vitro. Furthermore, the anti-proliferative effect of the drug can be reversed by the addition of uridine to the culture medium. These r esults suggest that inhibition of uridine biosythesis appears to be a mechanism by which LFM exerts anti-proliferative effects on both lymph ocytes and smooth muscle cells, and this dual action may be responsibl e for its efficacy in preventing GVD in vivo.