Open Access Highly Accessed Research article

Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists

Haïfa Hamdi1, Xavier Mariette2, Véronique Godot1, Karin Weldingh3, Abdul Monem Hamid4, Maria-Victoria Prejean1, Gabriel Baron5, Marc Lemann6, Xavier Puechal7, Maxime Breban8, Francis Berenbaum9, Jean-Charles Delchier10, René-Marc Flipo11, Bertrand Dautzenberg12, Dominique Salmon13, Marc Humbert4, Dominique Emilie114* and the RATIO (Recherche sur Anti-TNF et Infections Opportunistes) Study Group

Author Affiliations

1 INSERM UMR-S764, Service d'Hépato-Gastro-Entérologie and Service de Microbiologie-Immunologie Biologique, Hôpital Antoine Béclère, Assistance Publique – Hôpitaux de Paris (AP-HP), Institut Paris-Sud sur les Cytokines, Université Paris-Sud, INSERM U764, 32 rue des Carnets, 92140, Clamart, France

2 Service de Rhumatologie, Hôpital Bicêtre, AP-HP, Université Paris-Sud, INSERM U802, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France

3 Department of Infectious Disease and Immunology, Statens Serum Institut, Copenhagen S, 5 Artillerivej, 2300 Denmark

4 Service de Pneumologie, Hôpital A. Béclère, AP-HP, Université Paris-Sud, 157 rue de la Porte-de-Trivaux, 92140 Clamart, France

5 Département d'Epidémiologie, Biostatistique et Recherche Clinique, Groupe Hospitalier Bichat Claude-Bernard, AP-HP, Université Paris VII, INSERM U738, 46 rue Henri-Huchard, 75018 Paris, France

6 Service de Gastro-entérologie, Hôpital St. Louis, AP-HP, 1 avenue Claude-vellefaux, 75475 Paris, France

7 Service de Rhumatologie, Centre hospitalier du Mans, 194 avenue Rubillard, 72037 Le Mans, France

8 Service de Rhumatologie, Hôpital A. Paré, AP-HP, 9 avenue Charles-de-Gaulle, 92100 Boulogne, France

9 Service de Rhumatologie, Hôpital St. Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France

10 Service de Gastro-entérologie, Hôpital H. Mondor, AP-HP, 51 rue du Maréchal de Lattre de Tassigny, 94400 Créteil, France

11 Service de Rhumatologie, Hôpital C. Huriez, rue Michel Polonovski, 59037 Lille, France

12 Service de Pneumologie, Hôpital Pitié-Salpétrière, AP-HP, 83 boulevard de l'Hôpital, 75013 Paris, France

13 Service de Médecine interne et maladies infectieuses, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France

14 Service de Microbiologie – Immunologie Biologique, Hôpital A. Béclère, AP-HP Université Paris-Sud,, 157 rue de la Porte-de-Trivaux, 92140 Clamart, France

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Arthritis Research & Therapy 2006, 8:R114  doi:10.1186/ar1994

Published: 19 July 2006

Abstract

Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-α treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-γ. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-α treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-γ-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-γ release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-γ upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.