Mycobacterium tuberculosis (M.tb.) infection is epidemic in New York City among HIV-infected, homeless, intravenous drug users, and immigrants rising 42% over the past two years reaching a rate five times the national average. This epidemic is concentrated in minorities: 59% are African-American, and 26% are Hispanic. The TB case rate in Asians is 47/105 similar to the NYC average. The highest NYC incidence is 508/105 in African-American males ages 35-44 which is 53 times the national average. To address this epidemic, we propose a clinical study in TB- diseased humans targeting the pathophysiology of cytokine molecules in the lung. We hypothesize that IL-1beta and TNF-alpha are released in exaggerated quantities attracting inflammatory cells to sites of disease and inciting a granulomatous response. In HIV+ infected individuals, we propose a disrupted cytokine network associated with advanced AIDS and CD4+ <50/ul associated with fewer and more poorly-formed granulomas. We will perform bronchoalveolar lavage of sites of radiographic disease and compare cytokines to uninvolved pulmonary sites and peripheral blood mononuclear cells. We propose to study 100 active TB patients and 100 age-matched controls with varying presentations of pulmonary TB and to stratify by HIV infection. We will obtain tissue and utilize cytospins to evaluate the cellular distribution of cytokine molecules using immunohistochemistry and in situ hybridization. We will save bronchoalveolar lavage supernatants and mRNA to study the role of the other cytokines (IL-6, IL-8, IFN-gamma) to decipher complex cytokine network in tuberculosis. We will perform a clinical trial on 50 tuberculosis patients receiving chemotherapy stratified by HIV infection comparing cytokines at the start of treatment, 6-8 weeks after therapy begins, and 6 months later to establish the course of cytokines in tuberculosis patients with drug-sensitive organisms in a directly observed therapy program. These studies will provide an integrated model of how cytokines direct the granulomatous response to M.tb. and will provide the rationale for modulating cytokines in new therapies to accelerate phagocytosis and killing of M.tb. These studies will be critically important to health of minorities most severely afflicted with tuberculosis disease.
