Murine experimental autoimmune encephalomyelitis (EAE) is an experimentally induced, CD4+ T cell-mediated autoimmune disease directed against components of central nervous system (CNS) myelin. Because of similarities in clinical presentation and histopathology, EAE has long served as an animal model for the human demyelinating disease multiple sclerosis (MS). There has thus been intense interest in understanding the destructive immune responses occurring in both of these diseases in order to apply that understanding toward the design of specific immunotherapeutic treatments. The relapsing-remitting clinical course of MBP-induced EAE (R-EAE) in SJL/J mice has made it an ideal system to study the cellular and molecular mechanisms of disease pathogenesis and remittance, and to study the efficacy and mechanisms of specific immunoregulation for both prevention and treatment of this clinically relevant autoimmune disease. We thus propose to continue our studies addressing the temporal acquisition, effector role, epitope specificity. T cell receptor (TcR) usage, and lymphokine profile of both peripheral and CNS T cell-mediated immune (CMI) responses during the induction and relapsing episodes of active and adoptive MBP-induced R-EAE in SJL/J mice. Comparison of the disease course during these two forms of R-EAE [i.e., prolonged antigen/CFA stimulation in active disease vs. effector cell (efferent) stimulation in adoptive disease] and in response to a single epitope (MBP 84-104) vs. multiple epitopes (intact MBP) will be examined. A major emphasis will be the extension of our preliminary results to further define the apparent role in disease progression of sequential T cell responses against myelin antigens distinct from that which initiated the disease process. Responses against new myelin epitopes are apparently recruited as a result of myelin destruction during the acute phase of disease and mediate subsequent paralytic relapses. New studies will be instituted to examine the possible immunological mechanisms responsible for disease remittance with an emphasis on determining the in vivo role of costimulation signals and pattern of lymphokine gene expression within the CNS. Lastly, we will continue our current productive studies examining the effects and mechanisms of specific immune tolerance of effector encephalitogenic T cell clones in vitro and in vivo (employing i.v. injected neuroantigen-coupled syngeneic splenocytes) for treatment of clinical disease, and the differential effects of tolerance on neuroantigen-specific immune responses (e.g., lymphokine production profiles, DTH, Ab, and T cell proliferative responses). These studies should lead to a better understanding of the fine specificity, immunopathologic role, and molecular mechanisms of immunoregulation of MBP-specific T cell-mediated immune responses which should be applicable to the understanding and treatment of human MS and other CD4+ T cell- mediated immune diseases.
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