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 cytokines/adhesion molecules in the lung. We hypothesize that IL-1beta, TNF-alpha, and IL-6 are released in exaggerated quantities attracting inflammatory cells to sites of disease and inciting a granulomatous response. Furthermore, increased amounts of IFN-gamma and prime alveolar macrophages, and in concert with the other cytokines up-regulate adhesion molecules ICAM and VCAM on macrophages forming granulomata. 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 sties 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 HIV infection. We will obtain tissue and utilize cytospins to evaluate the cellular distribution of cytokines/adhesion molecules using immunohistochemistry and in situ hybridization. We have a transgenic mouse model of the IFN-gamma receptor knockout that we will infect with M.tb. to study cytokine/adhesion molecule response. These studies will provide an integrated model of how cytokines and adhesion molecules 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.
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