Longterm objectives are to study the perturbations of immunoregulation that are associated with infection by the pathogenic yeast, Histoplasma capsulatum (Hc). Studies of experimental pulmonary infection in mice will focus on the flux of lymphocyte subpopulations within infected lungs at serial intervals after intranasal inoculation by means of flow microfluorometry and immunohistological techniques. Antigen- specific vs non-specific recruitment of lymphocytes to infected lungs will be studied. These findings will be correlated with other experiments to assay production of Interleukin I and Interleukin II by cells from infected lung during the course of infection. The role played by T-L3T4+ helper/inducer cells in host defense against Hc infection and in modulation of the granulomatous inflammatory response will be examined by administration of the anti L3T4 monoclonal antibody GK 1.5. Studies on the interactions between unopsonized Hc yeasts and human monocyte-derived macrophages will be carried out to define further the importance of a glycorprotein surface receptor on M0 as the major site for binding of Hc to macrophages. More particularly, the role of the common B chain of the family of adherence glycoproteins CR3/LFA-1/P150-,95 will be determined. Factors governing phagocytosis and killing of Hc yeasts will be analyzed with emphasis on the regulatory effects of Interferon y, fibronectin, and phorbal myristate acetate. Ultrastructural studies will be performed by electron microscopy to examine for the first time, the fate of Hc within human macrophages. Mechanisms by which the organism appears to evade killing will be explored with emphasis on intra-phagosomic events. In humans, possible quantitative abnormalities of immunoregulatory cell populations of peripheral blood will be examined by flow microfluorometry. Functional properties of regulatory cell subsets in peripheral blood will be studied by in vitro techniques with respect to production of the cytokines IL-1 and IL-2 and INFy in response to specific and nonspecific stimuli. Similar studies will be performed on cells by bronchoalveolar lavage of patients with pulmonary histoplasmosis.
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