Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D-3

1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] inhibits production of IL- 12, a cytokine involved in the development of Th1 cells and in the pathogen esis of Th1-mediated autoimmune diseases. Here, we show that 1,25(OH)(2)D-3 and a non-hypercalcemic analogue are selective and potent Inhibitors of Th 1 development in vitro and in vivo without inducing a deviation to the Th2 phenotype. Administration of 1,25(OH)(2)D-3 or its analogue prevents chroni c-relapsing experimental allergic encephalomyelitis (CR-EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (MOG(35-55)) in Bi ozzi AB/H mice. The inhibition of EAE induction is associated with a profou nd reduction of MOG(35-55)-specific proliferation and Th1 cell development. Importantly, the non-hypercalcemic analogue also provides long-term protec tion from EAE relapses induced by immunization with spinal cord homogenate when administered fora short time at symptom onset or even after the first peak of disease. Neuropathological analysis shows a reduction of inflammato ry infiltrates, demyelinated areas and axonal loss in brains and spinal cor ds of treated mice. These results indicate that inhibition of IL-12-depende nt Th1 cell development is associated with effective treatment of CR-EAE an d suggest the feasibility of an approach based on low molecular weight inhi bitors of IL-12 production in the treatment of multiple sclerosis.