An improved understanding of the factors contorlling host susceptibility to Pneumocystis carinii could provide novel therapeutic modalities directed against this opportunistic pathogen. Our laboratory utilizes immunodeficient mouse models of P. Carinii pneumonia to study susceptibility to this organism, modeling the immune deficits present in HIV-infected individuals. Using these immunodeficient mouse models of P. Carinii pneumonia, we confirmed the roles of both CD4+ and CD8+ T cells in host defense against P. Carinii. Both CD4+ and CD8+ T cells are likely to control susceptibility to P. Carinii by elaboration of cytokines. Recent information shows that both of these T cell subsets can express either Th1 or Th2 cytokine repertoires. In an increasing number of model systems, it is apparent that the balance between susceptibility and defense does not depend on single cytokines with isolated actions. Rather, coordinated responses, precisely modulated in intensity and in sequence, control susceptibility. In preliminary data presented in this application, we characterize Th1 and Th2 cytokine production in the lungs of immunocompetent and immunodeficient mice after P. Carinii inoculation. We demonstrate differential, time-dependent patterns of cytokine production in vivo. Furthermore, we have successfully used mice deleted of specific cytokine genes (""""""""knockout"""""""" mice) to examine suceptibility to P. Carinii in vivo. Based o these data, we hypothesize that coordinated Th1 and Th2 responses are required for successful defense against p. Carinii, requiring early Th2-like responses and late Th1-like responses. There are four specific objectives: (1) to determine the cellular sources of cytokines responsible for successful defense against or susceptibility to P. Carinii in vivo; (2) to determine whether cytokine blockade can alter defense against or susceptibility to P. Carinii in vivo; (3) to isolate P. Carinii-specific CD4+ T cells with specific cytokine profiles in vitro and to determine whether these cells maintain their cytokine profiles in vivo; and (4) to determine whether reconstitution with CD4+ T cells of defined repertoire alters susceptibility to infection in vivo. These powerful animal models allow us to test the roles of cytokines in control of susceptibility to P. Carini using in vivo approaches that model human P. Carinii pneumonia. Ultimately, these studies can be extended to develop therapeutic strategies directed against this important opportunistic pathogen.
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