IL-4 INDEPENDENT IL-13 MEDIATED PROTECTIVE IMMUNITY

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Gastrointestinal nematodes of the genus Trichuris cause great morbidity and increased susceptibility to infectious agents in humans. Immune protection against Trichuris infection has been shown to be T cell-dependent and associated with IgE elevations and mastocytosis. We have used the natural murine parasite, Trichuris muris, as a model for understanding the development of the protective response. In our studies, we have recently identified a novelty pathway leading to worm expulsion in this parasite. Blocking T cell costimulation, with the B7 antagonist, CTLA4lg, triggers immune deviation from a host protective type 2 immune response characterized by elevations in IL-4 and IL-13 elevations. Additional blockade of IFN-gamma restores the host protective response, although IL-4 levels remain inhibited. Further studies show that the IL-4 independent protective response that can occur following IFN-gamma blockade is IL-13 dependent, suggesting that IL-13 can mediate host protection in the absence of a type 2 IL-4 dominant immune response. In these studies, we propose to analyze the regulation of IL-13 expression and function following B7 blockade of the T. muris mucosal in vivo immune response addressing the following specific aims: 1) identify the cell lineage that produces IL-13 when B7 interactions and IL-4 production are blocked; 2) examine the differentiation pathway leading to IL-13 production during the IFN-gamma dominant response; 3) determine the mechanism of IFN-gamma modulation of IL-13 effector function.