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Am J Clin Exp Immunol 2013;2(1):124-134
Original Article
Tumor necrosis factor neutralization combined with chemotherapy
enhances Mycobacterium tuberculosis clearance and reduces lung
pathology
Marie-Laure Bourigault, Rachel Vacher, Stéphanie Rose, Maria L Olleros, Jean-Paul Janssens, Valerie FJ Quesniaux ,
Irene Garcia
UMR7355, CNRS, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orleans,
France; Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Switzerland; Division
of Pneumology, HUG, University of Ge-neva, Switzerland
Received January 23, 2013; Accepted February 7, 2013; Epub February 27, 2013; Published March 9, 2013
Abstract: Tuberculosis (TB) is a major health problem requiring sustained immunity to inhibit Mycobacterium
tuberculosis growth and appropriate antimicrobial therapy to prevent dissemination and drug resistance. Cell-mediated
immune responses to M. tuberculosis involve the activation of cytokines such as Tumor Necrosis Factor (TNF) which is
critical for granuloma formation and host resistance against TB. TNF inhibition, used as therapy for the treatment of
inflammatory diseases, disrupts granuloma allowing replication of mycobacteria which may increase the efficacy of TB
chemotherapy. To test this hypothesis mice infected with M. tuberculosis were treated with isoniazid (INH) and rifampicin
(RMP) in the presence or absence of Enbrel, a soluble TNF receptor antagonist during three phases of M. tuberculosis
infection. Inhibition of TNF with Enbrel augmented the efficacy of TB chemotherapy as shown by enhanced mycobacterial
clearance from the lung of acute and established infection as well as in chronically infected mice. Furthermore, TNF
inhibition significantly reduced lung pathology as compared to TB chemotherapy alone. Therefore, the experimental data
suggest that TB chemotherapy may be more effective in the presence of a TNF inhibitor, which may be relevant to
eradicate mycobacteria during chronic M. tuberculosis infection or reactivation. (AJCEI1301002).
Keywords: Mycobacterium tuberculosis, chemotherapy, isoniazid (INH), rifampicin (RMP), tumor necrosis factor (TNF),
TNF inhibitors, granu-lomas
Address correspondence to: Irene Garcia, Département de Pathologie et Immunologie, CMU - 1 rue Michel Servet -
CH-1211 Genève 4. Phone: 022 379 5779; Fax: 022 3795746; E-mail: Irene.garcia-gabay@unige.ch
Original Article
Tumor necrosis factor neutralization combined with chemotherapy
enhances Mycobacterium tuberculosis clearance and reduces lung
pathology
Marie-Laure Bourigault, Rachel Vacher, Stéphanie Rose, Maria L Olleros, Jean-Paul Janssens, Valerie FJ Quesniaux ,
Irene Garcia
UMR7355, CNRS, Orleans, France; Experimental and Molecular Immunology and Neurogenetics, University of Orleans,
France; Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Switzerland; Division
of Pneumology, HUG, University of Ge-neva, Switzerland
Received January 23, 2013; Accepted February 7, 2013; Epub February 27, 2013; Published March 9, 2013
Abstract: Tuberculosis (TB) is a major health problem requiring sustained immunity to inhibit Mycobacterium
tuberculosis growth and appropriate antimicrobial therapy to prevent dissemination and drug resistance. Cell-mediated
immune responses to M. tuberculosis involve the activation of cytokines such as Tumor Necrosis Factor (TNF) which is
critical for granuloma formation and host resistance against TB. TNF inhibition, used as therapy for the treatment of
inflammatory diseases, disrupts granuloma allowing replication of mycobacteria which may increase the efficacy of TB
chemotherapy. To test this hypothesis mice infected with M. tuberculosis were treated with isoniazid (INH) and rifampicin
(RMP) in the presence or absence of Enbrel, a soluble TNF receptor antagonist during three phases of M. tuberculosis
infection. Inhibition of TNF with Enbrel augmented the efficacy of TB chemotherapy as shown by enhanced mycobacterial
clearance from the lung of acute and established infection as well as in chronically infected mice. Furthermore, TNF
inhibition significantly reduced lung pathology as compared to TB chemotherapy alone. Therefore, the experimental data
suggest that TB chemotherapy may be more effective in the presence of a TNF inhibitor, which may be relevant to
eradicate mycobacteria during chronic M. tuberculosis infection or reactivation. (AJCEI1301002).
Keywords: Mycobacterium tuberculosis, chemotherapy, isoniazid (INH), rifampicin (RMP), tumor necrosis factor (TNF),
TNF inhibitors, granu-lomas
Address correspondence to: Irene Garcia, Département de Pathologie et Immunologie, CMU - 1 rue Michel Servet -
CH-1211 Genève 4. Phone: 022 379 5779; Fax: 022 3795746; E-mail: Irene.garcia-gabay@unige.ch
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