Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: Possible role for limiting pathology

Reactivation of latent tuberculosis contributes significantly to the incide nce of disease caused by Mycobacterium tuberculosis, The mechanisms involve d in the containment of latent tuberculosis are poorly understood. Using th e low-dose model of persistent murine tuberculosis in conjunction with MP6- XT22, a monoclonal antibody that functionally neutralizes tumor necrosis fa ctor alpha (TNF-alpha), we examined the effects of TNF-alpha on the immunol ogical response of the host in both persistent and reactivated tuberculous infections. The results confirm an essential role for TNF-alpha in the cont ainment of persistent tuberculosis. TNF-alpha neutralization resulted in fa tal reactivation of persistent tuberculosis characterized by a moderately i ncreased tissue bacillary burden and severe pulmonic histopathological dete rioration that was associated with changes indicative of squamous metaplasi a and fluid accumulation in the alveolar space. Analysis of pulmonic gene a nd protein expression of mice in the low-dose model revealed that nitric ox ide synthase was attenuated during MP6-XT22-induced reactivation, but was n ot totally suppressed. Interleukin-12p40 and gamma interferon gene expressi on in TNF-alpha -neutralized mice was similar to that in control mice. In c ontrast, interleukin-10 expression was augmented in the TNF-alpha -neutrali zed mice. In summary, results of this study suggest that TNF-alpha plays an essential role in preventing reactivation of persistent tuberculosis, modu lates the pulmonic expression of specific immunologic factors, and limits t he pathological response of the host.