P011 TNF inhibition combined with chemotherapy for experimental tuberculosis improves pulmonary bacterial clearance and reduces pathology
Introduction TNF plays an important role in host immunity to M. tuberculosis infection and contributes to granuloma formation. TNF inhibition has been shown to disorganize pulmonary granulomas and to reactivate tuberculosis in certain patients. Chemotherapy for tuberculosis requires long and difficult treatments with reduced patient compliance. To determine whether TNF inhibition can be an advantage for the efficacy of anti-TB drugs to eliminate intracellular mycobacteria shortening the duration of chemotherapy, we compared the effects of co-administration of anti-TNF treatments and anti-TB drugs with those obtained with anti-TB drugs alone using a murine model of M. tuberculosis pulmonary infection. Methods Mice were infected with M. tuberculosis and treated with isoniazid (INH) and Rympamycin (RMP) alone or in combination with a TNF inhibitor (Enbrel), or with Enbrel alone, to determine whether TNF neutralization may improve chemotherapy for tuberculosis. The effect of co-administration of TNF blocker and therapy for M. tuberculosis treatments was evaluated during acute and chronic M. tuberculosis infections. Determination of lung bacterial load and pulmonary pathology was performed at different time points after stopping treatments. Results There was a reduction in pulmonary bacterial load and an improvement of pathology in mice co-treated with INH/RMP plus Enbrel compared to mice with chemotherapy alone during acute infection. During M. tuberculosis chronic infection, we observed that the effects of the chemotherapy combined with anti-TNF enhanced bacterial elimination and decreased pulmonary pathology compared to the TB therapy alone. Conclusion These data suggest that the combination of anti-TNF and therapy for M. tuberculosis improves chemotherapy and shortens the duration of the treatment which is an important clinical issue.