Murine chronic-relapsing experimental allergic encephalomyelitis (R-EAE) follows a progressive or relapsing-remitting course of paralysis. R-EAE 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 the human demyelinating disease multiple sclerosis (MS) make it an ideal animal model for the study of immunoregulatory aspects of MS. We propose to examine the neuroantigen specificity of T cell-mediated immune (CMI) throughout the clinical course of R-EAE and to examine the conditions and mechanisms by which the induction and/or expression of R-EAE can be modified following monoclonal antibody immunotherapy and following the induction of neuroantigen-specific immunological tolerance. The relative contribution of CMI responses to various components of the myelin membrane (e.g. myelin basic protein (MBP), proteolipid protein (PLP), galactocerebroside (GC), and myelin-associated glycoprotein (MAG)) to both the initial clinical signs of disease and to relapsing episodes of R-EAE induced by priming with whole spinal cord homogenate in complete Freund's adjuvant will be studied. The mechanisms by which disease induction is inhibited by monoclonal antibodies directed against MHC class II-restricted T cells (helper/delayed-type hypersensitivity) and exacerbated by monoclonal antibodies directed against MHC class I-restricted T cells (cytotoxic/suppressor) will also be investigated. The major effort will be devoted to expanding our preliminary studies dealing with disease modulation via the induction of neuroantigen- specific immunological tolerance. The relative effects of antigen-specific immune tolerance and suppressor T cell induction on clinical and histopathological disease parameters and neuroantigen-specific CMI responses will be assessed in mice tolerized via the iv injection on neuroantigen-coupled syngeneic splenocytes. These studies should lead to a better understanding of the fine specificity, immunopathologic role, and immunoregulation of T cell-mediated immune responses to various neuroantigens in murine EAE which may be applicable to the understanding and treatment of human MS.
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