TNF-alpha blockade impairs in vitro tuberculous granuloma formation and down modulate Th1, Th17 and Treg cytokines

Tuberculosis (TB) is a granulomatous disease that has affected humanity for thousands of years. The production of cytokines, such as IFN-gamma and TNF-alpha, is fundamental in the formation and maintenance of granulomas and in the control of the disease. Recently, the introduction of TNF-alpha-blocking monoclonal antibodies, such as Infliximab, has brought improvements in the treatment of patients with chronic inflammatory diseases, but this treatment also increases the risk of reactivation of latent tuberculosis. Our objective was to analyze, in an in vitro model, the influence of Infliximab on the granulomatous reactions and on the production of antigen-specific cytokines (TNF-alpha, IFN-gamma, IL-12p40, IL-10 and IL-17) from beads sensitized with soluble Bacillus Calmette-Guerin (BCG) antigens cultured in the presence of peripheral blood mononuclear cells (PBMC) from TB patients. We evaluated 76 individuals, with tuberculosis active, treated and subjects with positive PPD. Granuloma formation was induced in the presence or absence of Infliximab for up to 10 days. The use of Infliximab in cultures significantly blocked TNF-alpha production (p <0.05), and led to significant changes in granuloma structure, in vitro, only in the treated TB group. On the other hand, there was a significant reduction in the levels of IFN-gamma, IL-12p40, IL-10 and IL-17 after TNF-alpha blockade in the three experimental groups (p <0.05). Taken together, our results demonstrate that TNF-alpha blockade by Infliximab directly influenced the structure of granuloma only in the treated TB group, but negatively modulated the production of Th1, Th17 and regulatory T cytokines in the three groups analyzed.