REVERSAL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS BY A SOLUBLE PEPTIDE VARIANT OF A MYELIN BASIC-PROTEIN EPITOPE - T-CELL RECEPTOR ANTAGONISM AND REDUCTION OF INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION

An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87-99), is a major target of T cells in lesions of multiple scleros is (MS) and in experimental allergic encephalomyelitis (EAE). T cells found in EAE lesions bear the same amino acids in the third complement ary determining region of the T cell receptor (TCR) as those found in MS lesions. We analyzed the trimolecular interactions between MBP p87- 99, class II major histocompatibility complex (MHC), and TCR, and desi gned soluble inhibitors for therapy. F, N, I, and V at positions 90, 9 2, 93, and 94 interact with MHC, whereas K, T, and P at positions 91, 95, and 96 interact with TCR. The peptides, p87-99[95T>A] and p87-99[9 6P>A] could compete more effectively with p87-99 for binding to MHC an d could antagonize the in vitro response of T cells to p87-99 more eff ectively than p87-99[91K>A]. However, only p87-99[91K>A] prevented and reversed EAE, indicating that the extent of MHC or TCR competition do es not predict success in treating EAE. To elucidate the mechanism of inhibition of EAE, draining lymph node cells from rats immunized with the native peptide alone or together with each of the three TCR antago nists were challenged in vitro with p87-99. Administration of p87-99[9 1K>A], but not p87-99 [95T>A] or p87-99[96P>A], reduced the production of tumor necrosis factor (TNF)-alpha and interferon (IFN) gamma. IFN- gamma and TNF-alpha are two cytokines that are critical in the pathoge nesis of EAE and MS.