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Lopez-Casillas, F; Mata-Espinosa, DA; Mendoza-Rodriguez, V; Aguilar-Leon, D; Rosales, R; Hernandez-Pando, R (2008)

THERAPEUTIC EFFECT OF RECOMBINANT ADENOVIRUS ENCODING INTERFERON-GAMMA IN A MURINE MODEL OF PROGRESSIVE PULMONARY TUBERCULOSIS

MOL THER 16(6):1065-1072
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We constructed recombinant adenoviruses encoding murine interferon-gamma ( AdIFN gamma) and tested its therapeutic efficiency in a well characterized model of progressive pulmonary tuberculosis ( TB) in Balb/ c mice, infected through the trachea with the laboratory drug-susceptible H37Rv strain or multidrug-resistant ( MDR) clinical isolate. When the disease was in a late phase, 2 months after infection, we administered by intratracheal cannulation a single dose [ 1.7 x 10(9) plaque forming units ( pfu)] of AdIFN gamma or the control adenovirus. Groups of mice were killed at different time-points and the lungs were examined to determine bacilli colony forming units ( CFU), cytokine/ chemokine gene expression, and CD4/ CD8 subpopulations, and also subjected to automated histomorphometry. In comparison with the control group, after 2 weeks of treatment and during the next 6 months, AdIFN gamma-treated animals infected with either the H37Rv strain or the MDR strain showed significantly lower bacilli loads and tissue damage ( pneumonia), higher expressions of IFN-gamma, tumor necrosis factor ( TNF), and inducible nitric oxide synthase ( iNOS), and bigger granulomas. When compared with the results from conventional chemotherapy or AdIFN gamma treatment alone, the combined treatment with AdIFN gamma plus conventional chemotherapy shortened the time taken for reduction of bacillary load. This shows that gene therapy with AdIFN gamma efficiently reconstituted the protective immune response and controlled the progress of pulmonary TB produced by MDR or non-MDR strains.