Beneficial effects of leflunomide on cardiac myosin-induced experimental autoimmune myocarditis in rats

Abstract

The protective and therapeutical potential of a novel immunomodulatory agent, leflunomide, has been demonstrated in several experimental models of autoimmunity reactions leading to transplant rejection, as well as the therapy of patients with rheumatoid arthritis. in this study, the effects of leflunomide on experimentally induced autoimmune myocarditis (EAM) were investigated. Genetically susceptible DA rats were immunized with porcine cardiac myosin in complete Freund's adjuvant. The course of the disease was examined (on day 8, 16, 21 and 34) by macroscopic and microscopic scoring, heart weight/body weight ratio was determined and immunohistochemical analysis of inflammatory cell infiltrates was conducted. Eight days after disease induction, only slightly elevated expression of adhesive molecules on the interstitial and vascular endothelial cells were observed otherwise no microscopic signs of the inflammation existed. On day 16, numerous inflammatory cells infiltrated the myocardium. By day 21, the severity of myocarditis was substantially increased and was accompanied by extensive necrosis. After 34 days, decreased number of infiltrated cells was detected together with myocardial necrosis. Effects of leflunomide were evaluated by two treatment protocols. Rats immunized with cardiac myosin were injected i.p. with leflunomide's active metabolite, A 771726, at a dose of 10 mg/kg/day either during the first 6 days, or starting from day 14 and ending a: day 20 after disease induction. Efficacy of leflunomide treatment was determined on day 21 of EAM development Results demonstrated that early leflunomide treatment inhibited the inflammatory reaction, while late treatment significantly reduced EAM progression. Leflunomide may be considered a potent therapeutical tool for autoimmune myocarditis.