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Infection and Immunity, March 2001, p. 1847-1855, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1847-1855.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Effects of Tumor Necrosis Factor Alpha on Host Immune Response in Chronic Persistent Tuberculosis: Possible Role for Limiting Pathology

Vellore P. Mohan,1,2 Charles A. Scanga,3 Keming Yu,1,2 Holly M. Scott,3 Kathryn E. Tanaka,4 Enders Tsang,1,2 Ming Chih Tsai,1,2 JoAnne L. Flynn,3,5,* and John Chan1,2,*

Departments of Medicine,1 Microbiology and Immunology,2 and Pathology,4 Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461, and Departments of Molecular Genetics and Biochemistry3 and Medicine,5 University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Received 15 June 2000/Returned for modification 21 July 2000/Accepted 20 November 2000

Reactivation of latent tuberculosis contributes significantly to the incidence of disease caused by Mycobacterium tuberculosis. The mechanisms involved in the containment of latent tuberculosis are poorly understood. Using the low-dose model of persistent murine tuberculosis in conjunction with MP6-XT22, a monoclonal antibody that functionally neutralizes tumor necrosis factor alpha (TNF-alpha ), we examined the effects of TNF-alpha on the immunological response of the host in both persistent and reactivated tuberculous infections. The results confirm an essential role for TNF-alpha in the containment of persistent tuberculosis. TNF-alpha neutralization resulted in fatal reactivation of persistent tuberculosis characterized by a moderately increased tissue bacillary burden and severe pulmonic histopathological deterioration that was associated with changes indicative of squamous metaplasia and fluid accumulation in the alveolar space. Analysis of pulmonic gene and protein expression of mice in the low-dose model revealed that nitric oxide synthase was attenuated during MP6-XT22-induced reactivation, but was not totally suppressed. Interleukin-12p40 and gamma interferon gene expression in TNF-alpha -neutralized mice was similar to that in control mice. In contrast, interleukin-10 expression was augmented in the TNF-alpha -neutralized mice. In summary, results of this study suggest that TNF-alpha plays an essential role in preventing reactivation of persistent tuberculosis, modulates the pulmonic expression of specific immunologic factors, and limits the pathological response of the host.

* Corresponding authors. Mailing address for JoAnne L. Flynn: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1240 Biomedical Science Tower, Pittsburgh, PA 15261. Phone: (412) 624-7743. Fax: (412) 624-1401. E-mail: joanne{at}pitt.edu. Mailing address for John Chan: Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2678. Fax: (718) 430-8725. E-mail: jchan{at}aecom.yu.edu.

Infection and Immunity, March 2001, p. 1847-1855, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1847-1855.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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