Experimental allergic encephalomyelitis (EAE) is an autoimmune demyelinating disease that serves as a mo] -for the human disease Multiple Sclerosis. In EAE, the proinflammatory myelin-reactive T cells that mediate clinical disease represent the primary targets for therapeutic intervention. Intravenous administration of Myelin: Basic Protein prior to immunization or during ongoing EAE results in tolerance induction (i.v. tolerance) and diminished clinical disease manifestations. This tolerance is mediated by multiple mechanisms, including immune deviation (Thl - Th2 shift), induction of apoptotic cell death, and decreased trafficking of activated pro-inflammatory cells to the central nervous system (CNS). In the proposed studies, we will focus on the immunological outcome of i.v. tolerance in the CNS. Infiltrating mononuclear cells from the CNS of tolerized and nontolerized animals will be obtained and analyzed with multiparametric flow cytometric analysis. We will compare the activation profiles, expression of costimulatory ligands, apoptosis and the production of the various pro-inflammatory (TNF-oc, IL-2, and IFN- about) and anti-inflammatory cytokines by the defined mononuclear cell populations (CD4+, CD8+, CDllb+, CDl9+ or NKl.l+ populations) infiltrating the CNS of tolerized and nontolerized animals. In addition, we will compare CNS-derived cells to those obtained from the periphery (spleen and lymph nodes). Trafficking and activation of transgenic T cells specific for MBP, as well as apoptosis induction, in tolerized and nontolerized animals will also be assessed. Finally, we will assess the mechanism whereby i.v. tolerance regulates chemokines and chemokine receptors systemically and locally within the CNS. These studies will further elucidate the mechanisms by which i.v. MBP induces tolerance and suppresses clinical disease in EAE and will provide a novel method for analyzing the migration and functional status of infiltrating cells in the CNS in particular and in target organs of other autoimmune diseases.
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