The long term goal of the studies proposed here is to understand the induction, function and regulation of Th2 and related immune responses (type 2 immune responses) during schistosomiasis mansoni. Th2 responses are believed to protect humans against the more severe effects of infection with schistosomes and against reinfection. Schistosome infection also induces Th2 responses in mice; it is the egg stage of the parasite that appears most responsible for stimulatng the Th2 response. Th2 cells develop from naive precursor Th cells. For this to occur the naive cell must be exposed to IL-4 either at the time, or shortly after the time it is first activated through its antigen recepto The First Specific Aim of the proposal will be directed towards identifying the cellular source of the IL-4 that is produced early (less than 24 h) in the response to schistosome eggs and determining whether or not the """"""""early IL-4"""""""" plays a role in Th2 response development. To detrmine whether in mice type 2 responses play a protective role during infection with schistosomes is the Second Specific Aim of the proposal. The Third Specific Aim of the proposal will be to understand the role played by type 1 CD8+ cells in the immunoregulatory processes that lead to the downmodulation of type 2 responses and associated immunopathology during the chronic phase of infection. The experiments will make extensive use of mice that carry disrupted (knockout) IL-4, IL-5, or Beta2M genes; monoclonal antibodies which neutralize cytokines; cell sorting; cell and antibody transfers from wild type mice to knockout animals; in vitro culture; cytokine measurements, and parastiological techniques to aassess intensity of infection. In addition to being of importance in schistosomiasis Th2 responses play important roles in allergies, some autoimmune diseases, susceptibility to certain protozoal and viral infections and resistance to intestinal helminth infections. Consequently, it is of the utmost importance to understand how Th2 responses develop and are regulated. The study of schistosomiasis in the mouse represents and excellent, relevant model withwhich to address these issues.
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