1,25-Dihydroxyvitamin D(3) Protects against Immune-Mediated Killing of Neurons in Culture and in Experimental Autoimmune Encephalomyelitis

Several studies have reported that low vitamin D levels are associated with an increased risk of developing multiple sclerosis (MS). As MS is an inflammatory disorder with degeneration of axons and neurons, we examined whether the biologically active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25D(3)), could protect against the T cell-mediated killing of human neurons in culture, and the axonal loss seen in mice with experimental autoimmune encephalomyelitis (EAE). Human neurons were exposed to activated human T lymphocytes and the loss of neurons was documented 24 hours later by counting the number of microtubule-associated protein-2 positive cells. Mice with EAE were harvested for counts of axonal profiles in the spinal cord. 1,25D(3) was exposed to T cells in culture or administered to mice from peak EAE clinical severity when axonal loss was already evolving. Activated T lymphocytes killed human neurons prominently within 24 hours but toxicity was significantly attenuated when T cells were exposed to 1,25D(3) prior to the co-culture. In EAE, 1,25D(3) treatment initiated from peak clinical severity reduced the extent of clinical disability and mitigated the progressive loss of axons. The reduction of axonal and neuronal loss by 1,25D(3) in the context of an inflammatory assault to the central nervous system is a potential contributor to the putative benefits of vitamin D in MS.