The importance of cell mediated immunity to T. gondii is well appreciated. Recent studies have indicated that immune cytokines are important in modulating the host response to parasite infection. Observations in our laboratories and others show that cytokines produced by the presumptive Th1 type T cell, in particular IFN-gamma, IL-2 and IL- 12, are able to enhance protection. Conversely, those immune cytokines associated with the Th2 response, in particular IL-4, IL-6 and especially IL-10, influence the development of immunopathogenic alterations in the infected host resulting in increased morbidity and mortality. We hypothesize that the balance between protective (Th1) and afflictive (Th2) response can be manipulated by specific cytokine antagonists. Accordingly, the overall specific aim of this proposal is to determine the role of those Th2 cytokines that influence the development of immunopathologic changes during acute and chronic experimental toxoplasmosis. Specific inhibitors of these cytokines will be used to alter the course of natural infection. The first specific aim is to determine in vitro the mechanisms by which these Th2 cytokines downregulate the host response. Emphasis will be directed toward the relative contribution of IL-10, IL-6 and IL-4 in this response. The spleen, lymph node and intraintestinal epithelial (IEL) cells responsible for production of these cytokines will be identified and characterized. We will determine whether the Th2 response can be altered by route, dose or parasite stage at the time of infection. The mechanism by which these T. gondii induced cytokines downregulate the host responder cells, including the ability of T. gondii to act as a superantigen, will be evaluated. The second specific aim will be to evaluate in vivo the ability of the Th2 cytokines to induce immunopathogenic changes in the vital organs of the infected host. The inflammatory cells - will be phenotyped and the quantity of cytokine mRNA measured by semi- quantitative methods. It will be determined if natural resistance or susceptibility to infection are due in part to differences in Th2 cytokine profiles. The Th2 cytokine profile induced by different parasite strains will be assessed. The final specific aim will be to determine if quantity of cytokine mRNA measured by semi-quantitative methods. It will be determined if natural resistance or susceptibility to infection are due in part to differences in Th2 cytokine profiles. The Th2 cytokine profile induced by different parasite strains will be assessed. The final specific aim will be to determine if neutralization of the Th2 cytokines, in particular IL-10, IL-6 and IL-4 alone or in combination with anti- toxoplasma drugs will provide an additive or synergistic effect for treatment of toxoplasmosis in murine model.
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