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

Soumya D. Chakravarty,^1, Guofeng Zhu,^2, Ming C. Tsai,^1,, Vellore P. Mohan,^1,2, Simeone Marino,³ Denise E. Kirschner,³ Luqi Huang,⁴ JoAnne Flynn,⁵ and John Chan^1,2*

Departments of Microbiology and Immunology,¹ Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York 10461,² Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan 48909,³ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China 100700,⁴ Departments of Molecular Genetics and Biochemistry and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261⁵

Received 24 July 2007/ Returned for modification 25 September 2007/ Accepted 2 January 2008

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.

Published ahead of print on 22 January 2008.

Editor: F. C. Fang

These authors contributed equally.

Present address: Department of Obstetrics and Gynecology, NYU School of Medicine, New York, NY 10016.

Present address: Florida Department of Health, West Palm Beach Branch Laboratory, West Palm Beach, FL 33402.