Delineation of the immunosuppressive effect exerted by 1,25-dihydroxyvitamin D3 upon the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis

The active metabolite of vitamin D, 1α,25-Dihyrdoxyvitamin D₃ (1,25-(OH)₂D₃), suppresses autoimmune disease in several animal models including experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. We report that 1,25-(OH) ₂D₃ is unable to prevent EAE in mice lacking the vitamin D receptor (VDR), the protein through which 1,25-(OH)₂D₃ exerts most if not all of its biological activities through. This eliminates the possibility that the immunosuppressive effect of 1,25-(OH)₂D ₃ occurs through a “non-genomic” action or through an undiscovered receptor. We next investigated EAE in mice lacking functional CD8+ T-cells, which is the cell type with the highest levels of VDR. While severity of EAE was increased in the CD8+ null mice, 1,25-(OH) ₂D₃ was still able to prevent disease. This study suggests that CD4+ T-cells are the target cell for immunosuppression of EAE by the actions of 1,25-(OH)₂D₃. We also investigated if this immunosuppressive effect was a direct result of the hormone or if it was an effect that was secondary to a 1,25-(OH)₂D₃-mediated rise in serum calcium. The amount of 1,25-(OH)₂D₃ needed to prevent disease is inversely related to the amount of calcium in the diet, and protection of EAE is only observed in animals with abnormally high levels of calcium present in the blood. To test if hypercalcemia independent of high doses 1,25-(OH)₂D₃ was immunosuppressive, we developed an animal model where serum calcium levels are increased by breakdown of bone mediated by parathyroid hormone (PTH). By developing this model in mice lacking the enzyme responsible for synthesizing 1,25-(OH)₂D₃, the P450 enzyme 25-hydroxyvitamin D-1α-hydroxylase, serum calcium levels were raised by PTH without increasing endogenous levels of the vitamin D hormone. Hypercalcemia generated this way protected against EAE in female mice but not male mice. This suggests that 1,25-(OH)₂D₃ does not directly function in the suppression of EAE in females. The fact that males are also not protected by 1,25-(OH)₂D₃ under 0 dietary calcium conditions suggest that this protection is indirect. This makes unlikely the use of vitamin D compounds as therapeutic agents for MS if EAE is truly a model of that disease.