PHARMACOLOGICALLY INDUCED REGRESSION OF CHRONIC TRANSPLANT REJECTION

Chronic rejection, characterized by a progressive obliterative arterio pathy, is a major cause of graft failure in long-surviving human trans plants for which there is no effective treatment. Leflunomide, an isox azol derivative, has been shown to be a novel immunomodulatory drug th at profoundly suppresses the immune response. In this study, 58 Fisher -344 rats received cardiac transplantation hom Lewis rats, All the rec ipients were given CsA at 2.5 mg/kg for 5 days postoperatively. Withou t further treatments, the arterial intima was progressively injured by mononuclear cell infiltration and Ab deposition. Smooth muscle cell a nd fibroblast proliferation in the intima became a predominant phenome non by day 90. CsA was ineffective in controlling the progress of arte rial intimal thickening when treatment began on day 30. Leflunomide at 5 mg/kg failed to control arterial intimal thickening by day 60 when therapy began on day 30. However, the progress of arterial intimal thi ckening was significantly inhibited by day 90 when the dosage of leflu nomide had been increased to 10 mg/kg on day 60. Combined therapy with leflunomide and CsA at 5 mg/kg for 30 days dramatically reversed the arterial thickening by day 60. After increasing the dosages of both le flunomide and CsA to 10 mg/kg on day 60, the combination therapy stead ily controlled the chronic rejection, Only the combination therapy sig nificantly down-regulated circulating antidonor IgM and IgG titers. In rat amooth muscle cell culture, this same drug combination had a syne rgistic inhibitory effect on proliferation. Therefore, the combination therapy of leflunomide and CsA could reverse and control the progress of chronic rejection, while leflunomide, at higher dosage as a monoth erapy, could stabilize chronic rejection in this model. The mechanism of the regression of chronic rejection by leflunomide and cyclosporine may be related to their in vitro abilities to control not only lympho cyte but smooth muscle cell proliferation, as well. The synergistic ef fect of these two drugs on vascular smooth muscle cell proliferation i n vitro may be an important part of this novel activity. This unique f eature holds intriguing possibilities for treating established chronic rejection.