The Animal Studies Core will have responsibility for in vivo testing of agents developed in Projects I, II, III, and IV for the treatment of cryptococcosis. The Animal Studies Core will evaluate several new approaches to the therapeutic management of cryptococcosis in AIDS patients. These approaches will include determining the anticryptococcal activity of i) neutrophil defensins (Project I, Selsted), ii) a variety of lymphokines used alone, in combination with each other, and in combination with known antifungal drugs (Project II, Edwards), iii) growth-regulating cryptococcal pheromones (Project III, Courchesne), and iv) anticryptococcal specific monoclonal antibodies (MAb)(Project IV, Kozel). A murine model utilizing BALB/c mice will be used to evaluate the efficacy of the proposed chemotherapeutics for the treatment of disseminated cryptococcosis. We have selected a murine model because i) mice can be readily infected, ii) disseminated cryptococcosis in the mouse produces a meningoencephalitis in a manner similar to cryptococcosis in the AIDS patient, iii) a large body of literature exists regarding antifungal therapy in this model, iv) the mouse is the best strategy for the large-scale evaluation of anticryptococcal agents that will be done in this Program Project, and v) the mouse is the human cryptococcosis. The disseminated infection will be produced by intravenous injection of highly encapsulated cryptococci.
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