Pleuropulmonary tuberculosis is an urgent world wide problem and is epidemic among individuals with HIV. A central host defense response against tuberculosis involves the recruitment of mononuclear phagocytes to the area of tuberculous inflammation leading to the sequestration of tubercle bacilli into granuloma and prevention of dissemination of infection. The initial response to tubercle bacilli is mediated through the activation of local non-immune cells that release chemokines to recruit peripheral blood monocytes. Monocyte chemoattractant protein-1 (MCP-1) is a recently described chemokine which plays a crucial role in granuloma formation by recruitment of monocytes. Regulatory factors affecting MCP-1 production are unknown. The investigators have developed a model of pleural tuberculosis in normal and CD4 depleted mice who are given intrapleural BCG. In preliminary data, CD4 depleted mice did not demonstrate a monocyte influx into the pleural space, did not develop granulomas on the pleural surface but developed disseminated infection with BCG. In contrast, control mice who had a monocyte response developed well defined granuloma without dissemination. IFN-F levels were elevated in pleural fluid of normal mice but undetectable in pleural fluid from CD4 depleted mice. In vitro pleural mesothelial cells stimulated by BCG produced significant quantity of MCP-1. Based on these preliminary data, the investigator hypothesizes that in TB pleurisy, local non-immune cells, the pleural mesothelial cells play a critical role in monocyte recruitment, granuloma formation and subsequent localization of mycobacteria by the production of MCP-1. The investigators will examine this hypothesis in the pleural tuberculosis mouse model as well as in in vitro cultures of pleural mesothelial cells and BCG. The regulatory role of Th1 cytokine IFN-g in mesothelial cell production of MCP-1 will be evaluated. The proposed studies will determine the effectiveness of the local pleural mesothelial cells in the early response to tubercle bacilli and the role of MCP-1 in granuloma formation and prevention of dissemination of infection.
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