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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017339-06
Application #
3127164
Study Section
Bacteriology and Mycology Subcommittee 1 (BM)
Project Start
1980-09-01
Project End
1986-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Newman, S L; Gootee, L; Bucher, C et al. (1991) Inhibition of intracellular growth of Histoplasma capsulatum yeast cells by cytokine-activated human monocytes and macrophages. Infect Immun 59:737-41
Deepe, G S; Bullock, W E (1990) Immunological aspects of fungal pathogenesis. Eur J Clin Microbiol Infect Dis 9:567-79
Schnur, R A; Newman, S L (1990) The respiratory burst response to Histoplasma capsulatum by human neutrophils. Evidence for intracellular trapping of superoxide anion. J Immunol 144:4765-72
Newman, S L; Bucher, C; Rhodes, J et al. (1990) Phagocytosis of Histoplasma capsulatum yeasts and microconidia by human cultured macrophages and alveolar macrophages. Cellular cytoskeleton requirement for attachment and ingestion. J Clin Invest 85:223-30
Gomez, A M; Bullock, W E; Taylor, C L et al. (1988) Role of L3T4+ T cells in host defense against Histoplasma capsulatum. Infect Immun 56:1685-91
Bullock, W E; Wright, S D (1987) Role of the adherence-promoting receptors, CR3, LFA-1, and p150,95, in binding of Histoplasma capsulatum by human macrophages. J Exp Med 165:195-210
Baughman, R P; Kim, C K; Vinegar, A et al. (1986) The pathogenesis of experimental pulmonary histoplasmosis. Correlative studies of histopathology, bronchoalveolar lavage, and respiratory function. Am Rev Respir Dis 134:771-6
Deepe Jr, G S; Taylor, C L; Harris, J E et al. (1986) Modulation of cellular immune responses in mice with disseminated histoplasmosis by recombinant interleukin-2. Infect Immun 53:6-12
Deepe Jr, G S; Smith, J G; Sonnenfeld, G et al. (1986) Development and characterization of Histoplasma capsulatum-reactive murine T-cell lines and clones. Infect Immun 54:714-22
Baughman, R P; Kim, C K; Bullock, W E (1986) Comparative diagnostic efficacy of bronchoalveolar lavage, transbronchial biopsy, and open-lung biopsy in experimental pulmonary histoplasmosis. J Infect Dis 153:376-7

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