title: Tumor necrosis factor blockade in chronic murine tuberculosis enhances granulomatous inflammation and disorganizes granulomas in the lungs.
abstract: Tumor necrosis factor (TNF) is a prototypic proinflammatory cytokine that contributes significantly to the development of immunopathology in various disease states. A complication of TNF blockade therapy, which is used increasingly for the treatment of chronic inflammatory diseases, is the reactivation of latent tuberculosis. This study used a low-dose aerogenic model of murine tuberculosis to analyze the effect of TNF neutralization on disease progression in mice with chronic tuberculous infections. Histological, immunohistochemical, and flow cytometric analyses of Mycobacterium tuberculosis-infected lung tissues revealed that the neutralization of TNF results in marked disorganization of the tuberculous granuloma, as demonstrated by the dissolution of the previously described B-cell-macrophage unit in granulomatous tissues as well as by increased inflammatory cell infiltration. Quantitative gene expression studies using laser capture microdissected granulomatous lung tissues revealed that TNF blockade in mice chronically infected with M. tuberculosis leads to the enhanced expression of specific proinflammatory molecules. Collectively, these studies have provided evidence suggesting that in the chronic phase of M. tuberculosis infection, TNF is essential for maintaining the structure of the tuberculous granuloma and may regulate the granulomatous response by exerting an anti-inflammatory effect through modulation of the expression of proinflammatory mediators.
authors.affiliation: Department of Medicine and Microbiology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, F406, Bronx, NY 10461, USA.
authors.forename: Soumya D
authors.initials: SD
authors.lastname: Chakravarty
authors.forename: Guofeng
authors.initials: G
authors.lastname: Zhu
authors.forename: Ming C
authors.initials: MC
authors.lastname: Tsai
authors.forename: Vellore P
authors.initials: VP
authors.lastname: Mohan
authors.forename: Simeone
authors.initials: S
authors.lastname: Marino
authors.forename: Denise E
authors.initials: DE
authors.lastname: Kirschner
authors.forename: Luqi
authors.initials: L
authors.lastname: Huang
authors.forename: Joanne
authors.initials: J
authors.lastname: Flynn
authors.forename: John
authors.initials: J
authors.lastname: Chan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006099:Granuloma / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha