Tuberculosis is endemic among patients with AIDS and follows an aggressive course with poor localization of mycobacteria into granuloma and widespread infection. Granulomas are monocyte rich collections of cells which derive from the circulating peripheral blood monocyte (PBMC). Monocytes are recruited to the site of tuberculous infection by the interaction of C-C chemokines, (mainly monocyte chemoattractant protein-1, MCP- 1) and monocyte expression of the CCR2 receptor. It is the hypothesis of this proposal that recruitment and retention of the monocyte at the site of tuberculous infection is predicated not only on local release of MCP-1 but on the expression of CCR2 receptor on PBMC. CD4 depletion alters monocyte recruitment and retention by altering the in vivo expression of CCR2 on PBMC and macrophages. This inhibitory effect of CD4 depletion is due to the relative imbalance between Thi and Th2 cytokines. We have developed a model of pleural tuberculosis in CD4 -1- and CD4 +/+ mice to evaluate the Th1/Th2 regulation of the CCR2 receptor on PBMC. We will evaluate our hypothesis in our model of pleural tuberculosis in vivo as well as in vitro in PBMC and elicited pleural macrophages (PM).
Our specific aims are 1) To determine the in vivo moncyte influx, granulonia formation, mycobacterial clearance and mortality utilizing our model of pleural tuberculosis in a CD4 knockout mouse model, CD4 -/- mice and control, wild type CD4 +1+/- mice. 2) To determine the in vivo effect of CD4 depletion on the compartmentalized and peripheral expression of CCR2 receptor on PBMC and PM and the regulatory role of Th1 (IL2, IL-12) and Th2 (11-10, JL-4) cytokines inCD4 -/- and CD 4 +/+ mice with pleural tuberculosis. 3) To determine the in vitro molecular and cellular regulation of CCR2 expression in PBMC and PM in the presence of Th1 and Th2 cytokines and 4) To determine the role of tubercie bacilli stimulated pleural mesothelial cell derived cytokines in the regulation of CCR2 receoptor on peripheral blood monocytes (PBMC) and pleural niacrophages (PM) in vivo and in vitro. Understanding the mechanism of regulation of CCR2 receptor by Th1 and Th2 cytokines may help us discern the pathophysiology of pleuro-pulmonary tuberculosis seen in patients with AIDS and may help develop therapeutic modalities that augment host-defense responses.
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