RESUMO

We constructed recombinant adenoviruses encoding murine interferon-gamma (AdIFNgamma) 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 AdIFNgamma 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, AdIFNgamma-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 AdIFNgamma treatment alone, the combined treatment with AdIFNgamma plus conventional chemotherapy shortened the time taken for reduction of bacillary load. This shows that gene therapy with AdIFNgamma efficiently reconstituted the protective immune response and controlled the progress of pulmonary TB produced by MDR or non-MDR strains.

Assuntos

Adenoviridae/genética , Terapia Genética/métodos , Interferon gama/genética , Tuberculose Pulmonar/genética , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Progressão da Doença , Interferon gama/biossíntese , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Células-Tronco , Fator de Necrose Tumoral alfa/biossíntese

RESUMO

We constructed recombinant adenoviruses encoding murine interferon-γ (AdIFNγ) 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 × 109 plaque forming units (pfu)] of AdIFNγ 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, AdIFNγ-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-γ, tumor necrosis factor (TNF), and inducible nitric oxide synthase (iNOS), and bigger granulomas. When compared with the results from conventional chemotherapy or AdIFNγ treatment alone, the combined treatment with AdIFNγ plus conventional chemotherapy shortened the time taken for reduction of bacillary load. This shows that gene therapy with AdIFNγ efficiently reconstituted the protective immune response and controlled the progress of pulmonary TB produced by MDR or non-MDR strains.