Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes

In certain animal models of autoimmunity the isoxasol derivative leflunomid e has been reported to exert a protective effect against autodestruction. I n the present study, the immunomodulatory potential of the main metabolite of leflunomide, A77 1726, in experimentally induced autoimmune diabetes was investigated. The disease was induced in genetically susceptible CBA/H mic e by multiple low doses of streptozotocin (MLD-SZ, 40 mg/kg per day, given intraperitoneally for 5 consecutive days). Effects of leflunomide were eval uated by two treatment protocols: mice treated with MLD-SZ were injected in traperitoneally with A77 1726 for 10 consecutive days, either during the fi rst 10 days of the disease (early treatment), or starting from day 10 after disease induction (late treatment). Disease manifestations defined by hype rglycaemia, mononuclear infiltration into pancreas, expression of interfero n-gamma (IFN-gamma) and inducible nitric oxide synthase (iNOS) and destruct ion of the islets of Langerhans were reduced in a dose-dependent fashion af ter early treatment with A77 1726 (dose range of 5-35 mg/kg per day). Moreo ver, late treatment with the high dose of the drug (25 mg/kg per day), star ted when the autoimmune disease was already apparent, arrested progression of ongoing inflammatory response. Analysis of the effects of A77 1726 on th e adhesive interactions of spleen-derived or peripheral blood-derived monon uclear cells from MLD-SZ-treated and normal mice demonstrated that the drug inhibits both ex vivo and in vitro spontaneous mononuclear cell aggregatio n, thus suggesting that an important component of leflunomide's immunomodul atory action is suppression of adhesive interactions. These results demonst rate both preventive and therapeutic effects of leflunomide in a model of M LD-SZ-induced diabetes and suggest that the drug may be considered a potent therapeutic tool for autoimmune inflammatory disorders, including diabetes .