Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory demyelinating disease of the CNS that serves as a model for human multiple sclerosis (MS). A relapsing-remitting form of EAE (R-EAE) is induced in SJL/J mice following active immunization with either the major encephalitogenic determinants of proteolipid protein (PLP 139-151) or myelin basic protein (MBP84-104) or by the adoptive transfer of peptide-specific T cells. During the previous funding period we have made the critical observation that disease progression (relapses) in this peptide-induced R-EAE models are due primarily to the recruitment of T cell responses against non-cross reactive endogenous myelin epitopes on the same or different myelin proteins (intramolecular or intermolecular epitope spreading). Since numerous human autoimmune diseases (e.g., MS, rheumatoid arthritis, SLE) display relapsing-remitting or chronic- progressive courses, epitope spreading has very important implication for the pathogenesis for these human diseases and for the potential application of specific forms of immunotherapy to their treatment. We propose to continue to test the hypothesis that immune responses to endogenous myelin epitopes play the predominant role in progression of R- EAE and that these T cells are primed as a result of exposure to myelin epitopes released during acute CNS damage. The myelin epitope specificity, precursor frequency, receptor repertoire, cytokine (Th1/Th2) profile, and encephalitogenic potential of peripheral (Specific Aim 1) and CNS-resident (Specific Aim 2) CD4+ T cells at varying stages of the R-EAE disease process will be assessed.
Specific Aim 3 will determine the underlying mechanisms behind the temporal progression of immune responses to the various myelin epitopes in the peptide-induced EAE models by assessing the T cell precursor frequency, MHC class II binding affinity, and efficiency of processing of encephalitogenic myelin epitopes on PLP, MBP, MOG, and MAG. In addition, the relative ability of various potential CNS-resident APCs (astrocytes, microglia, infiltrating macrophages, and cerebrovascular endothelial cells) derived from the primary cultures and isolated from mice with ongoing EAE to express relevant co-stimulatory molecules and to process and present encephalitogenic myelin epitopes to a panel of myelin epitope-specific T cell clones and hybridomas will be assessed. These studies should enhance our understanding of the mechanisms of induction of epitope spreading and the effector role of these responses in the chronic pathogenesis of CNS autoimmune diseases. In addition, these studies will provide vital information relative to the use of specific immunoregulation for the treatment of pre-existing autoimmune disorders.
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