Several lines of evidence argue that T cell-mediate autoimmunity plays a role in the pathogenesis of multiple sclerosis (MS). The precise nature of the antigen eliciting the autoimmune attack on the myelin sheath is not known, but in-vivo-activated, clonally expanded lymphocytes reactive with myelin basic protein (MBP) have been demonstrated in MS peripheral blood. Injection of MBP into susceptible strains of mice together with immunologic adjuvants results in the induction of experimental autoimmune encephalomyelitis (EAE), a chronic relapsing disease with extensive demyelination. EAE, induced by CD4+ cells of the Th1 type, is viewed as the best model currently available for testing of MS therapeutic regimens. We have reported that the oral administration of MBP exerts a profoundly suppressive effect on EAE in Lewis rats. Rats fed MBP exhibit a striking inhibition of EAE clinical neurologic signs, reduced CNS histopathologic changes, and suppressed T and B cell responses specific for MBP. Two mechanisms have been put forward to explain orally induced tolerance in the EAE model - clonal anergy and active suppression. In applying oral tolerance to the treatment of chronic disease like MS, it will be necessary to determine whether an ongoing autoimmune process can be suppressed after initiation of immunologic injury. We have obtained preliminary data indicating that orally administered MBP, given either before challenge or at the time of disease onset, is acute effective in suppressing relapses of EAE. Therefore, with our background in the oral tolerance field and new preliminary data relative to chronic, relapsing disease, we propose to address several aims relative to our underlying hypothesis that oral tolerance is mediated through clonal anergy or deletion and is capable of halting the progression of ongoing autoimmune disease. First, we will determine the relative efficacy of oral neuroantigen administration in relapsing EAE. In these studies, we will focus on the specificity of tolerance and the timing of tolerogen administration relative to disease using whole neuroantigens (MBP, PLP, myelin). Effectiveness of these neuroantigens at the time of disease appearance, or during a remission period or at the time of relapse will be tested. Second, we will determine the fine specificity of oral tolerance in the B10.PL mouse using MBP Peptides. Tolerogenicity of encephalitogenic as well as non- encephalitogenic peptides and MBP peptide analogs will be studied. Third, the mechanism(s) of suppression of relapsing EAE will be studied by examining suppressor T cells, clonal anergy, clonal deletion, and shifts in cytokine profile as possible candidates. These studies will be aided by the availability of a Valpha2/VBeta8.2 transgenic mouse. Therefore, at the conclusion of these experiments, the boundaries of the oral tolerance therapeutic approach in its alteration of the long-term course of a chronic inflammatory disease will be defined.
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