Abstract
Interferon gamma (IFN-γ) production is a critical step of antituberculosis (anti-TB) immune response. The purpose of this study was to determine the influences of biologics, including the interleukin (IL)-6 receptor-inhibitor tocilizumab (TCZ), and tumor necrosis factor (TNF) antagonists infliximab (INF) and etanercept (ETA), on Mycobacterium tuberculosis (MTB) antigen-induced IFN-γ production. MTB antigen (ESAT-6 and CFP-10)-induced IFN-γ-releasing assay was performed with or without addition of biologics (TCZ, ETA, and INF) using whole blood from patients with active TB. ETA and INF inhibited IFN-γ production in a dose-dependent manner. In whole blood from TB patients, ESAT-6 stimulated significant production of IFN-γ (1.30 ± 1.95 IU/ml), and TCZ did not inhibit IFN-γ production (1.56 ± 1.88 IU/ml). IFN-γ production by ESAT-6 was inhibited by ETA and INF (0.98 ± 1.74, 0.75 ± 1.66 IU/ml, respectively). CFP-10 stimulated significant production of IFN-γ (1.46 ± 1.60 IU/ml), and TCZ did not inhibit IFN-γ production (1.51 ± 1.77 IU/ml). IFN-γ production by CFP-10 was inhibited by ETA and INF (0.91 ± 0.99, 0.72 ± 0.88 IU/ml, respectively). TCD did not inhibit MTB antigen-induced IFN-γ production. As IFN-γ production is important in antimycobacterial host defenses, the minimal influence of TCZ on IFN-γ-releasing assay suggests a low risk of latent TB infection reactivation during tocilizumab therapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis. 2003;3:148–55.
Jacobs M, Togbe D, Fremond C, Samarina A, Allie N, Botha T, et al. Tumor necrosis factor is critical to control tuberculosis infection. Microbes Infect. 2007;9:623–8.
Lalvani A. Diagnostic tuberculosis infection in the 21st century. Chest. 2007;131:1898–906.
Hamdi H, Mariette X, Godot V, Weldingh K, Hamid AM, Prejean MV, Baron G, Lemann M, Puechal X, Breban M, Berenbaum F, Delchier JC, Flipo RM, Dautzenberg B, Salmon D, Humbert M, Emilie D; RATIO (Recherche sur Anti-TNF et Infections Opportunistes) Study Group. Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists. Arthritis Res Ther. 2006;8:R114.
Saliu OY, Sofer C, Stein DS, Schwander SK, Wallis RS. Tumor-necrosis-factor blockers: differential effects on mycobacterial immunity. J Infect Dis. 2006;194:486–92.
Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007;66:1162–7.
Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Alten R; OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study). A double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987–97.
Furst DE, Wallis R, Broder M, Beenhouwer DO. Tumor necrosis factor antagonists: different kinetics and/or mechanisms of action may explain differences in the risk for developing granulomatous infection. Semin Arthritis Rheum. 2006;36:159–67.
Diehl S, Rincón M. The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 2002;39:531–6.
Salvana EM, Cooper GS, Salata RA. Mycobacterium other than tuberculosis (MOTT) infection: An emerging disease in infliximab-treated patients. J Infect. 2007;55:484–7.
Korn T, Oukka M, Kuchroo V, Bettelli E. Th17 cells: effector T cells with inflammatory properties. Semin Immunol. 2007;19:362–71.
Acknowledgments
This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation and also funded by Wyeth Japan, Mitsubishi Tanabe Pharma Corporation, and Chugai Pharmaceutical Co., Ltd.
Conflict of interest statement
Atsushi Ogata has received speaking fees from Mitsubishi Tanabe Pharma Corporation and Chugai Pharmaceutical Co., Ltd (less than $10,000). Tadamitsu Kishimoto holds a patent for tocilizumab. Toshio Tanaka has received speaking fees from Chugai Pharmaceutical Co., Ltd (less than $10,000).
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Ogata, A., Mori, M., Hashimoto, S. et al. Minimal influence of tocilizumab on IFN-γ synthesis by tuberculosis antigens. Mod Rheumatol 20, 130–133 (2010). https://doi.org/10.1007/s10165-009-0243-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10165-009-0243-4