RETINOID TREATMENT OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS - IL-4 PRODUCTION CORRELATES WITH IMPROVED DISEASE COURSE

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by central nervous system inflammation and demyelinatio n. Retinoids regulate cell differentiation and growth by binding to an d activating retinoic acid receptors, which seem to be nuclear transcr iption factors. The effect of retinoids on chronic relapsing EAE produ ced by the transfer of myelin basic protein (MBP)-specific lymph node cells (LNC) was studied. All-trans-retinoic acid (tRA) inhibited the p roliferation of MBP-specific LNC in vitro. However, the capacity of th ese cells to transfer EAE was markedly reduced by concentrations of tR A that only mildly inhibited T cell proliferation. The presence of tRA during in vitro MB P-specific LNC activation resulted in a considerab le increase in IL-4 mRNA, whereas mRNA for IL-2, TNF-alpha, and IFN-ga mma was decreased. Increased IL-4 also was detected in culture superna tants. However, the presence of a neutralizing Ab to IL-4 (11B11) duri ng MBP-specific LNC activation in vitro did not reverse the inhibition of encephalitogenicity caused by tRA. The administration of retinoids in vivo resulted in an improved clinical course, even when given afte r disease onset. These findings suggest that T cell activation in the presence of tRA results in the development of T cells of the Th2 pheno type, which, in turn, might be responsible for the decrease in the enc ephalitogenicity of MBP-specific T cells. The modulation by retinoids of an immune response dominated by Th1-like T cells to one in which th e protective cytokines of Th2-like cells predominate may have potentia l relevance for human demyelinating diseases such as multiple sclerosi s.