The recent tuberculosis (TB) epidemic in the United States has been fueled by several factors, including underfunded public health programs, overcrowding in urban homeless shelters and prisons, continuing immigration to the United States from countries with a high incidence of TB, and the HIV epidemic. The increased susceptibility to tuberculosis infection and disease among HIV-infected patients is directly related to impaired host immunity. In recent years, key components of the host response to tuberculosis have been elucidated, and it now seems increasingly clear that a Th1-type T-lymphocyte response is associated with a good outcome in TB patients. In addition, there is increasing evidence that HIV-infected patients have impaired TH1 number and function, with a resultant deficiency of interferon-gamma (IFN-g), a key effector cytokine in host immunity in tuberculosis. This project proposes to study the role of T-helper cells in human tuberculosis, with a specific focus on the role of IFN-g in the pathogenesis of tuberculosis in patients with and without HIV infection. This project will study the role of Th1 cells in general and IFN-g in particular both at the clinical level as well as at the basic level so that we might understand both the regulation of gene expression of this cytokine as well as its interaction with other cytokines and inflammatory effector cells in the lung itself, both in HIV positive and negative patients.
The specific aims are to: 1) modulate the Th phenotype in BAL cells and HIV-1 replication in active pulmonary tuberculosis by aerosol treatment with interferon-gamma; 2) investigate mechanisms by which IFN-gamma contributes to host defense against tuberculosis in HIV-positive and HIV-negative persons; and 3) analyze mechanisms of gene regulation effected by IFN-gamma treatment.
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