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. This latter factor may be the most significant, particularly in areas where HIV is most common among injection drug users, as is the case in New York City, where at least 33% of TB cases occur in HIV-infected persons. In younger patients, co-infection between TB and HIV is even more prevalent: fully 60% of TB patients in the 25-44 year-old age group in New York City have co- existing HIV infection. The increased susceptibility to TB infection and disease among HIV-infected patients is directly related to impaired host immunity. In recent years, we and others have elucidated key components of the host response to TB, 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 TB. We hypothesize that aerosolized IFN-g will promote a Th1 response mediated by interferon-responsive factors leading to reduced HIV-1 replication and a propitious clinical outcome. To test this hypothesis we propose to use the powerful research tool of bronchoalveolar lavage (BAL) to sample the inflammatory milieu of lung segments with TB and compare results to uninvolved segments of the same patient and normal controls.
Specific Aim 1 will compare pre- to post- BAL specimens in 30 HIV-1/TB co-infected patients, with half randomized to receive aerosolized IFN-g and the endpoints being measurements of Th1 response and HIV-1 viral load.
Specific Aim 2 will investigate mechanisms by which IFN-g contributes to host defense, including studies of co-stimulatory molecules, MHC class II and inducible nitric oxide synthase.
Specific Aim 3 will analyze molecular mechanisms of IFN-g signalling by Richard Pine, Ph.D. (Public Health Research Institute), including STAT molecules, their phosphorylation, IFN-g regulatory factor 1, and class II transactivator. Findings from these studies will further characterize the local host response to M. tuberculosis in vivo and determine if the host response can be modulated, particularly in HIV-1/TB co-infected patients, by IFN-g, thus resulting in a more favorable clinical outcome.
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