Our goal is to design of T cell receptor and MHC blocking peptides with predictable properties that might be used therapeutically to treat multiple sclerosis. Originally we formulated a non-immunogenic peptide based on the based on the sequence of myelin basic protein (MBP) that binds to I-Au with much greater affinity relative to the encephalitogenic peptide Ac1-11 of MBP. This peptide reverses EAE, and even prevents subsequent relapses, if given at the time that signs of EAE first begin to appear. We shall extend these findings to develop inhibitors of MHC and of TCR specific for MBP peptide 87-99 in the Lewis rat. The reason for pursuing inhibitors of the TCR and of MHC-binding of peptide 87-99, follows from some serendipitous finding regarding a major set of TCR rearrangements in MS brain lesions. We analyzed T cell receptor (TCR) gene rearrangements directly from MS brain plaques. Rearrange Vbeta 5.2 genes were detected in the brains of all patients who were HLA DR2. A common Vbeta t.2-Dbeta-Jbeta sequence in these MS brain plaques was identical to that described for the VDJ region of a Vbeta 5.2 T cell clone. This clone from an MS patient, who was HLA DR2, was cytotoxic for targets with MBP peptide 89-106. The deduced amino acid sequence of this VDJ rearrangement, LRG, was also described previously in T Cells, cloned from EAE lesions, which were specific for MBP peptide 87-99. VDJ sequences with specificity for this MBP epitope constitute a large fraction (40%) of the TRC Vbeta 5.2N(D)N rearrangements in MS lesions. The capacity of T cells with these VDJ sequences to cause EAE, and the prevalence of such sequences in demyelinated lesions, indicated that T cells with this rearranged TCR, may be critical in MS. We have analyzed the MBP peptide 87-99 to determine the putative interaction sites with MHC and with TCR. Based on these studies we have designed peptide analogues of MBP 87-99 that interfere with either MHC or TCR binding, including the LRG motif found in the CDR3 of TCR commonly transcribed in MS lesions. Some of these TCR antagonists prevent EAE. We thus plan to develop MBP analogues that interfere with TCR and MHC recognition of MBP peptide 87-99. We will test these antagonists to determine if they can reverse EAE after the first signs of disease have appeared. We shall also develop CD4+ T cell clones specific for human MBP peptide 87-99 and restricted to HLA DRB1*1501(DR2), and test whether the blockers from the Lewis rat system also block their human counterparts. Ultimately we would hope to apply these results to clinical trials in MS.
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