Resistance to pathogenic microorganisms involves a complex combination of humoral and cellular immunity. Dissection of the contribution of specific arms of the immune response in host resistance to infectious agents has relied primarily on the availability of mouse strains genetically deficient in particular cell types-e.g. the W/Wv mouse lacking mast cells, the beige mouse and motheaten mouse deficient in NK cells and the SCID and nude mouse lacking lymphocyte populations. However, most of these mutations are pleiotrophic, resulting in complex phenotypes, making the assignment of specific immune pathways for a particular pathogen difficult. To determine the role of antibody dependant effector cell mediated pathways in host resistance to pathogenic microorganisms, we have constructed a mouse strain genetically deficient in Fc receptors for IgG and IgE. This strain of mice, deficient in the gamma chain of Fc receptors for IgG and IgE, Fc-gamma-RIII and Fc-epsilon-RI, respectively, is deficient in receptors involved in ADCC mediated by NK, macrophages and neutrophils, in IgG stimulated phagocytosis of those cells and in IgE dependant mast cell effector pathways. These effector cells have been shown to have a primary role in host resistance to parasitic infections. Two well-defined parasitic organisms, Cryptococcus neoformans and Trinchinella spiralis will be used as models to investigate the role of FcR mediated pathways in host resistance. Mice genetically deficient in FcRs will be used to determine the role of Fc-gamma-R mediated ADCC by NK cells, macrophages and neutrophils in resistance to the fungal pathogen Cryptococcus neoformans and to the Fc-epsilon-RI dependant mast cell response to the nematode Trinchinella spiralis. In vitro ADCC and phagocytosis assays will be performed on IgG and lgE opsonized targets and in vivo challenge experiments will be employed to determine the contribution of these receptors in host resistance. These experiments will provide novel insights into the role of antibody mediated effector pathways in resistance to parasites by addressing the role of Fc receptor triggered responses in host resistance.
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