Proteolipid protein (PLP) is the major protein component of CNS myelin and appears to be a major target of immune responses both in murine models of experimental autoimmune encephalomyelitis (EAE) and perhaps in human multiple sclerosis (MS). A chronic-relapsing form of EAE (R-EAE) is induced in inbred SJL/J mice following either active immunization with intact PLP or the major encephalitogenic determinant of the PLP molecule which encompasses amino acids 139-151 (PLP139-151(s)), or the adoptive transfer of T cell lines/clones specific for the PLP139-151(s) epitope. PLP-induced R-EAE follows a relapsing-remitting course of paralysis and is characterized histologically by perivascular mononuclear cell-rich infiltrates of the white matter of the central nervous system (CNS) and areas of acute and chronic demyelination. The well-understood genetics of the murine host and the similarities in both clinical course and histopathology of murine R-EAE and MS make it an ideal animal model for the study of immunopathogenic and immunoregulatory aspects of MS. We propose to examine the neuroantigen specificity, effector phenotype, T cell receptor usage, and lymphokine-producing profile of both peripheral and CNS-infiltrating neuroantigen-specific T cell-mediated immune (CMI) responses throughout the relapsing clinical course of PLP-induced R-EAE to determine if epitopes different than that which induced the initial paralytic episode are targeted during clinical relapses. We also propose to examine the conditions and mechanisms by which the induction and/or expression of PLP-induced R-EAE can be specifically downregulated (following the induction of neuroantigen-specific immunological tolerance). In addition, aspects of the molecular pathogenesis of demyelination will be addressed by defining and comparing encephalitogenic and tolerogenic PLP epitopes, and determining the effects of in vivo and in vitro tolerance induction on the ability of encephalitogenic PLP139-151(S)-specific T cell clones to produce particular lymphokines and/or subsequently mediate clinical disease. These studies should lead to a better understanding of the fine specificity, immunopathologic role, and immunoregulation of PLP-specific T cell-mediated immune responses which may be applicable to the understanding and treatment of human MS.
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