MECHANISMS FOR REDUCED TH1 RESPONSES IN TUBERCULOSIS

University Of Texas Hlth Ctr At Tyler, Tyler TX

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Abstract

DESCRIPTION (Adapted from the applicant's abstract): Tuberculosis (TB) is a major cause of morbidity and mortality in HIV-infected persons throughout the world. This proposal will investigate the pathogenesis of reduced interferon (IFN)-gamma production in TB and enhance our understanding of the mechanisms for susceptibility to disease from intracellular pathogens that are common in HIV-infected persons. To test the hypothesis that soluble macrophage products and costimulatory molecule abnormalities reduce IFN-gamma production in TB patients, the applicant will study cells activated in vivo at the site of disease, PBMC cultured in vitro with M. tb, and interactions between T-cells and macrophages infected with M. tb. These complementary methods allow a comprehensive study of the mechanisms for reduced IFN-gamma production in TB. The applicant's aims are: 1) To determine the contribution of soluble macrophage products to reduced IFN-gamma production by T-cells. The applicant will measure relative levels of T-cell IFN-gamma and macrophage IL-10, IL-12 and TGF-beta at the site of disease, refine an in vitro system to evaluate the effects of macrophage products on IFN-gamma production. 2) To determine the mechanisms by which soluble macrophage products reduce IFN-gamma production. The applicant's preliminary data suggest that M. tb-induced IFN-gamma production by PBMC from TB patients is abnormally sensitive to downregulation by IL-10, and that T-cells from TB patients lack CREB-ATF DNA-binding proteins that normally enhance IFN-gamma gene transcription by binding to the promoter. The applicant will measure IL-10 receptor expression by macrophages and T-cells from the site of disease and blood of TB patients, determine the effects of monokines on expression of CREB-ATF DNA-binding proteins, as well as on IFN-gamma gene transcription rates and mRNA stability. 3) To evaluate the contribution of dysregulated costimulatory molecules to reduced IFN-gamma production. The applicant will evaluate the distribution of CTLA-4, CD28, B7-1 and B7-2 at the site of disease and in M. tb-stimulated PBMC, determine if infection of macrophages with live M. tb alters costimulatory molecule expression, and determine if modulation of costimulatory molecules enhances IFN-gamma production by M. tb-stimulated T-cells.