Marc Muller

Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D3

1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3] inhibits production of IL‐12, a cytokine involved in the development of Th1 cells and in the pathogenesis of Th1‐mediated autoimmune diseases. Here, we show that 1,25(OH)2D3 and a non‐hypercalcemic analogue are selective and potent inhibitors of Th1 development in vitro and in vivo without inducing a deviation to the Th2 phenotype. Administration of 1,25(OH)2D3 or its analogue prevents chronic‐relapsing experimental allergic encephalomyelitis (CR‐EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35 – 55 (MOG35 – 55) in Biozzi AB / H mice. The inhibition of EAE induction is associated with a profound reduction of MOG35 – 55‐specific proliferation and Th1 cell development. Importantly, the non‐hypercalcemic analogue also provides long‐term protection from EAE relapses induced by immunization with spinal cord homogenate when administered for a short time at symptom onset or even after the first peak of disease. Neuropathological analysis shows a reduction of inflammatory infiltrates, demyelinated areas and axonal loss in brains and spinal cords of treated mice. These resuls indicate that inhibition of IL‐12‐dependent Th1 cell development is associated with effective treatment of CR‐EAE and suggest the feasibility of an approach based on low molecular weight inhibitors of IL‐12 production in the treatment of multiple sclerosis.