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

PLoS One. 2018 Mar 15;13(3):e0194430. doi: 10.1371/journal.pone.0194430. eCollection 2018.

Abstract

Tuberculosis (TB) is a granulomatous disease that has affected humanity for thousands of years. The production of cytokines, such as IFN-γ and TNF-α, is fundamental in the formation and maintenance of granulomas and in the control of the disease. Recently, the introduction of TNF-α-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-α, IFN-γ, IL-12p40, IL-10 and IL-17) from beads sensitized with soluble Bacillus Calmette-Guérin (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-α 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-γ, IL-12p40, IL-10 and IL-17 after TNF-α blockade in the three experimental groups (p <0.05). Taken together, our results demonstrate that TNF-α 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors*
  • Cytokines / metabolism
  • Female
  • Granuloma / blood
  • Granuloma / drug therapy
  • Granuloma / metabolism
  • Humans
  • Infliximab / pharmacology*
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism
  • Th1 Cells / drug effects
  • Th1 Cells / metabolism
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism
  • Tuberculosis / blood
  • Tuberculosis / drug therapy
  • Tuberculosis / metabolism
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult

Substances

  • Cytokines
  • Tumor Necrosis Factor-alpha
  • Infliximab

Grants and funding

This work was supported by the FUNDAÇÃO DE AMPARO A PESQUISA DO ESTADO DE MINAS GERAIS to DAAS, JSC, CJO, VR; CAPES-Coordenação de Aperfeiçoamento de Pessoal de Nível Superior to HSC, MVS; Conselho Nacional de Desenvolvimento Científico e Tecnológico to VR, CJO, DRRB; CEFORES to DBRR. FUNEPU was in charge of the financial management. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.