The long-term objectives of this proposal are to elucidate immunosuppressive mechanisms operant in human pulmonary tuberculosis. The previous observations and preliminary data supported by AI-18471 support the following hypothesis: Discrete mycobacterial protein constituents selectively stimulate monocytes or alveolar macrophages to express cytokines involved in inflammation, immune induction and fibrosis (interleukin-1(IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF)] and potential mediators of immunosuppression [interleukin-2 receptor (IL- 2R), transforming growth factor-B1 (TGF-B1)]. The increased response of monocytes from patients with tuberculosis to such microbial factors in the initiating event in antigen-specific suppression. CD16 and Fc-gamma suppressor lymphocytes stimulated by mediators produced by monocytes, and by PPD, represent an efferent component of specific immunoregulatory circuits as they suppress responses of CD4 lymphocytes.
The specific aims to test the hypothesis are: 1) To characterize mycobacterial protein constituents which stimulate monocytes and alveolar macrophages to express proinflammatory cytokines (IL-1, IL-6, TNF) and IL-2R and to assess their induction of TGF-B1. 2) To identify the products of mycobacterial antigen-stimulated monocytes from patients with tuberculosis which suppress T-cell responsiveness; and 3) To enumerate and expand potentially suppressive lymphocyte subpopulations (CD16, Fc-gamma, gamma-delta T-cells) into cell lines and clones, and to assess their activation by products of monocytes, and mycobacterial constituents, and their suppression of CD4 responses. The experimental design uses the approaches of cellular immunology, immunochemistry, biochemistry and molecular biology. This is a health- related project.
