The centerpiece of the proposed studies is Phenolic Glycolipid I, a major Mycobacterium leprae specific antigen with a unique trisaccharide in which 3,6-di-O-Me-Beta-D-glucopyranose is the epitope, as determined by chemical dissection and the use of human leprosy IgM and monoclonal IgG. This proposal concerns the role of the epitone and of the lipid moiety of the antigen in cell mediated immunity and pathogenesis of leprosy. The thrust of the proposed experiments is that the phenolic glycolipid by virtue of its extraordinary bipolar nature functions operationally, on the one hand, as a hapten that can elicit delayed type hypersensitivity response which may be genetically determined and may lead to immunity after infection; on the other hand, it may act as an epitope which preferentially stimulates suppressor T cells that lead to immunological unresponsiveness to other M. leprae protein antigens. Moreover, the phenolic glycolipd, due to its diacylated phenolic phthiocerol substituent, may function as a major immunoregulatory molecule. Analogs of the phenolic glycolipid, such as artificial oligosaccharide protein antigens, will be synthesized and used to define the epitope recognized by T lymphocytes, by studying their functional expression (proliferation, delayed type hypersensitivity reaction, cytotoxicity) and by producing T cell clones to the glycolipid. The lipoidal diacylphthiocerol portion will be conjugated to protein antigens and its ability to alter the quality of the immune response, as determined by delayed type hypersensitivity and antibody response will also be examined. The outcome of this innovative approach should facilitate subsequent investigations of mechanisms of immunosuppression and pathogenesis and allow the design of a leprosy vaccine based on the remarkable phenolic glycolipids.
