Abstract
Multiple sclerosis (MS) is a complex neurodegenerative disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, neuroantigen‐specific, CD4^+^ T cell‐mediated autoimmune response. In support of the hypothesis that vitamin D~3~ may reduce MS risk and severity, we found that vitamin D~3~ and 1,25‐dihydroxyvitamin D~3~ (1,25‐(OH)~2~D~3~) inhibited induction of experimental autoimmune encephalomyelitis (EAE), an MS model. To investigate how 1,25‐(OH)~2~D~3~ could carry out anti‐inflammatory functions, we administered 1,25‐(OH)~2~D~3~ or a placebo to mice with EAE, and subsequently analyzed clinical disease, chemokines, inducible nitric oxide synthase (iNOS), and recruitment of dye‐labeled monocytes. The 1,25‐(OH)~2~D~3~ treatment significantly reduced clinical EAE severity within 3 days. Sharp declines in chemokines, inducible iNOS, and CD11b^+^ monocyte recruitment into the central nervous system (CNS) preceded this clinical disease abatement in the 1,25‐(OH)~2~D~3~‐treated animals. The 1,25‐(OH)~2~D~3~ did not directly and rapidly inhibit chemokine synthesis in vivo or in vitro. Rather, the 1,25‐(OH)~2~D~3~ rapidly stimulated activated CD4^+^ T cell apoptosis in the CNS and spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti‐inflammatory feedback loop. The activated inflammatory cells produce 1,25‐(OH)~2~D~3~, and this hormone subsequently enhances the apoptotic death of inflammatory CD4^+^ T cells, removing the driving force for continued inflammation. In this way, the sunlight‐derived hormone could reduce the risk of chronic CNS inflammation and autoimmune‐mediated neurodegenerative disease. © 2007 Wiley‐Liss, Inc.