HUMAN T-CELL RESPONSE TO MYELIN BASIC-PROTEIN PEPTIDE-(83-99) - EXTENSIVE HETEROGENEITY IN ANTIGEN RECOGNITION, FUNCTION, AND PHENOTYPE

Multiple sclerosis (MS) is considered a T cell-mediated autoimmune dis ease, and myelin proteins are the most likely candidate autoantigens. Based on experiments performed in experimental allergic encephalomyeli tis (EAE), innovative immunotherapies have been developed that target either the specific trimolecular: complex of encephalitogenic T cells, consisting of T-cell receptor (TCR), major histocompatibility complex (MHC; HLA in humans) class II molecule, and autoantigenic peptide, or the effector functions of these cells. To provide the basis for the t ransfer of these specific immunotherapies to MS, we extensively charac terized the human T-cell response to one major myelin epitope, the mye lin basic protein peptide (83-99). We analyzed restriction element, TC R usage and affinity, fine specificity, cytokine production, cytolytic activity, and expression of surface molecules on 41 T-cell clones (TC Cs) derived from MS patients and normal controls. We demonstrate a hig h degree of complexity of recognition patterns as well as of functiona l phenotypes among T cells responding to the same epitope. In contrast to results from animal models, these findings indicate that the desig n of epitope-based specific immunotherapies for MS is more difficult t han previously thought.