The long-term obejctives of this project are to study the disturbances of immuno-regulation that are associated with infection by the pathogenic yeast, Histoplasma capsulatum (Hc). Studies of disseminated histoplasmosis (D-HPL) in inbred mice, will characterize the soluble suppressor and helper factors that are generated by spleen cells of infected animals and determine their respective mechanism(s) of action on target cells. The possible biological activities of these factors in vivo also will be examined. The immunopathology of experimental pulmonary histoplasmosis will be studied during the disease process by immunohistological staining of cell populations within granulomatous inflammation at serial intervals and by similar staining of cells in bronchoalveolar lavage (BAL) fluid. Traffic of specificity sensitized T cells and unsensitized control T cells to sites of granulomatous inflammation will be measured. Immunopharmacologic studies will seek to abrogate suppressor cell activity in mice with D-HPL and, if successful, will determine the biological significance thereof in respect to host resistance to challenge by Hc. Immunotherapeutic approaches to be explored include the production and the administration to infected mice of monoclonal antibodies with activity against suppressor cell subpopulations and, modulation of the cellular infiltrate within granulomas by the angiotensin converting enzyme inhibitor, captopril. 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 including reverse hemolytic plaque assay and assays of cytokine production in response to specific and nonspecific stimuli. Similar studies will be performed on cells obtained by BAL patients with pulmonary histoplasmosis.
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