Evidence suggests that autoreactivity to myelin antigens may play a role in the demyelination and subsequent disease manifestations seen in multiple sclerosis (MS). Experimental allergic encephalomyelitis (EAE), an autoimmune disease resulting from a cell-mediated immune response to myelin basic protein (MBP), is frequently studied as a model for the MS disease process. The preliminary results set forth in this application demonstrate that EAE can be inhibited by the oral administration of MBP to Lewis rats. In feeding MBP in the presence of an enzyme inhibitor to retard its proteolysis in the trointestinal tract, we have observed a striking inhibition of EAE clinical signs as well as an antigen-specific suppression of the in vitro lymphocyte proliferative response following encephalitogenic challenge. In light of these results, we propose to ask the following questions: 1) What is the optimal means for inducing oral tolerance to MBP in rats? The amount of MBP necessary, the kinetics, the neuroantigen specificity, and the length of time tolerance can be demonstrated will be studied. 2) What portion of the MBP molecule is responsible for eliciting the suppressive effects? MBP fragments (1-37, 43-88, 89-169, 68-88) will be a) fed to Lewis rats prior to encephalitogenic challenge and b) utilized in the in vitro lymph node cell (LNC) proliferative assay to determine the relative suppressive determinant on the MBP molecule. 3) What is the mechanism of orally induced tolerance to MBP? Transfer studies will be carried out to localize the suppressive lymphoid compartment. Depending on the results, either cellular or humoral analyses will be undertaken to identify the suppressor cell or characterize the suppressive humoral factor. 4) Is orally induced tolerance to MBP effective in suppressing ongoing EAE? The effects of oral MBP, initiated concurrently with or at various times after encephalitogenic challenge, will be examined. The effect of oral MBP on the transfer of EAE mediated by MBP-specific T cell lines and on chronic relapsing EAE will be assessed. The fact that oral MBP requires no adjuvants, is a potent means for generation of systemic suppression, and most likely does not expose the systemic immune system to the entire encephalitogenic MBP molecule are distinct advantages. The studies proposed would investigate the mechanism and treatment modality for an MS clinical trial.
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