In certain animal models of autoimmunity the isoxasol derivative
leflunomide has been reported to exert a protective effect against autodestruction. In 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 mice by multiple low doses of
streptozotocin (MLD-SZ, 40 mg/kg per day, given intraperitoneally for 5 consecutive days). Effects of
leflunomide were evaluated by two treatment protocols: mice treated with MLD-SZ were injected intraperitoneally with
A77 1726 for 10 consecutive days, either during the first 10 days of the disease (early treatment), or starting from day 10 after disease induction (late treatment). Disease manifestations defined by hyperglycaemia, mononuclear infiltration into pancreas, expression of
interferon-gamma (IFN-gamma) and
inducible nitric oxide synthase (iNOS) and destruction of the islets of Langerhans were reduced in a dose-dependent fashion after early treatment with
A77 1726 (dose range of 5-35 mg/kg per day). Moreover, late treatment with the high dose of the
drug (25 mg/kg per day), started when the
autoimmune disease was already apparent, arrested progression of ongoing inflammatory response. Analysis of the effects of
A77 1726 on the adhesive interactions of spleen-derived or peripheral blood-derived mononuclear cells from MLD-SZ-treated and normal mice demonstrated that the
drug inhibits both ex vivo and in vitro spontaneous mononuclear cell aggregation, thus suggesting that an important component of
leflunomide's immunomodulatory action is suppression of adhesive interactions. These results demonstrate both preventive and
therapeutic effects of
leflunomide in a model of MLD-SZ-induced diabetes and suggest that the
drug may be considered a potent therapeutic tool for autoimmune inflammatory disorders, including diabetes.