Myelin basic protein (BP) is a potential autoimmune target in multiple sclerosis (MS) and in post-viral demyelinating states. Encephalitogenic sites on the BP molecule vary from species to species and even from strain to strain. Therefore, it is impossible to determine from animal studies which sites on the molecule may be encephalitogenic in humans. We have generated 40 BP-specific T cell clones from the peripheral blood of a patient with MS and are using them to identify T cell recognition sites on the molecule. Current data indicate that there are at least ten epitopes on the BP molecule that are recognized by human T cells. We will further define the epitopes recognized by our current clones and will generate new clones from additional patients with MS, from patients with post-viral demyelinating syndromes, and from normal subjects. Initial studies with each new clone will examine the proliferative responses against large fragments of the BP molecule. These fragments will be generated by limited thrombin digestion at position 97-98 of the human molecule and limited pepsin digestion at position 88-89 of the guinea pig molecule. Subsequent studies will evaluate the pattern of responses against a panel of xenogeneic BPs of known amino acid sequence. Once these studies have narrowed down the potential sites of T cell recognition, small peptic fragments and synthetic peptides will be used to fully define the epitopes in question. These clones will subsequently be used to evaluate cross- reactivity between BP and viral antigens, to examine genetic restriction patterns involved in BP recognition by T cells, to compare the patterns of reactivity among individual subjects and between patient groups, to evaluate for BP-specific cytotoxic activity, and to generate anticlonotypic monoclonal antibodies which may be used to identify idiotype-bearing T cells in MS pathologic material and which may be useful in suppressing anti- BP responses in vitro and in vivo. The clones may also be used to """"""""vaccinate' patients with MS, again in order to suppress a potential anti-BP immune response, with the possibility of successfully treating the disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunological Sciences Study Section (IMS)
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Georgetown University
Schools of Medicine
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