Mycobacterium tuberculosis (Mtb) infects one-third of the world's population and ranks seventh in terms of global morbidity and mortality. Patients with bilateral pulmonary tuberculosis (TB), cavitary disease, and persistently positive sputum smears pose a special risk for treatment failure and/or relapse. Under HL59832 we treated 11 active pulmonary TB patients with rIFN-gamma aerosol for one month, noting improvements in symptoms, chest radiographs, and declines in inflammatory cytokines. Also, there were striking declines in HIV-1 viral burdens in 5/5 HIV- l/TB coinfected patients. In bronchoalveolar lavage (BAL) cells we observed increased STAT-1 binding and IRF-1 and -9 binding activity post treatment. In preliminary data, we have been able to identify gene clusters induced/repressed in BAL cells by short-term rIFN-gamma aerosol treatment. Our goal is to now demonstrate clinical efficacy of long-term rIFN-gamma aerosol treatment in advanced, cavitary pulmonary TB, where the risk of failure/relapse is unusually high with standard treatment. We propose in Aim 1 a randomized, controlled clininical trial in 64 patients in a NYU/Bellevue - University of Cape Town subcontract using rIFN-gamma aerosol for 4 months in addition to standard treatment compared to standard treatment alone. Endpoints include percent failure/relapse, time to culture Mtb (including negative culture), and change in cavity size/CT-scan findings.
In Aim 2 we will evaluate the Thl response in blood and lung using flow cytometry, cytokine measurements and in vitro TB antigen challenge to characterize macrophage and lymphocyte responses to 4 months rIFN-gamma.
In Aim 3 we will endeavor to determine the molecular effects of aerosolized rIFN-gamma on TGF-beta, its receptor, and Smad signaling molecules, and downstream effectors including collagen, MMP1 and 9, and CTGF using real-time PCR, EMSAs, and immunoblots with Richard Pine, PhD (subcontract to the Public Health Research Institute).
In Aim 3 b we will pursue functional genomics to identify novel human gene targets of rIFN-gamma aerosol and DOTS during the course of treatment. This study is critical in developing efficacious treatment strategies for TB and demonstrating that rIFN-gamma ameliorates the lung fibrosis and destruction in advanced TB.
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