PREVENTION OF MURINE EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS - COOPERATIVE EFFECTS OF CYCLOSPORINE AND 1ALPHA,25-(OH)(2)D-3

The hormone 1 alpha,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) has immune modulatory activities in vitro and in vivo, and can prevent or delay the onset of experimental or spontaneous autoimmune diseases. At therapeutical doses, however, hypercalcemic side effects are found. The present experiments examined the effects of combined treatment with subtherapeutic doses of cyclosporine A (CsA) and 1,25(OH)(2)D-3 on the evolution of experimental autoimmune encephalomyelitis (EAE) in SJL mice. 1,25(OH)(2)D-3 at 5 mu g/kg body weight (given by i.p. injection every 2 days) prevented the appearance of paralysis in 70% of the treated mice. The treatment with 1,25(OH)(2)D-3 at 2 mu g/kg/2 days alone had less substantial protective effects (22% disease-free animals versus 5% in the control group). However, when this subtherapeutic dose was associated to treatment with a daily dose of CsA (2 or 5 mg/kg/day), which by itself was subtherapeutic (24 and 50% disease-free animals, respectively), the association of both drugs led to near-total protection (86% disease-free animals when combined with the highest dose of CsA). When an alternate day administration schedule (CsA at 10 mg/kg and 1,25(OH)(2)D-3 at 2 mu g/kg, each given on alternate days from day -3 to +19 after disease induction) was used, all treated mice were completely protected clinically and histologically. The two drugs also showed additive effects on serum osteocalcin and urinary calcium and desoxypyridinoline excretion, but not on serum calcium concentration. Our experiments demonstrate that 1,25(OH)(2)D-3 might be a potential dose-reducing agent for CsA in immunosuppressive therapy.