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Infect. Immun. doi:10.1128/IAI.01011-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs

Departments of Microbiology & Immunology and Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48909, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China, 100700 and Departments of Molecular Genetics & Biochemistry and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

^* To whom correspondence should be addressed. Email: jchan{at}aecom.yu.edu.

	Abstract

Tumor necrosis factor (TNF) is a prototypic pro-inflammatory cytokine that contributes significantly to the development of immunopathology in various disease states. A complication of TNF blockade therapy, 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 infection. Histological, immunohistochemical, and flow-cytometric analyses of Mycobacterium tuberculosis-infected lung tissues revealed that 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 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 pro-inflammatory molecules. Collectively, these studies have provided evidence suggesting that in the chronic phase of M. tuberculosis infection, TNF is essential in 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 pro-inflammatory mediators.