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Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists |
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| Authors: | Haïfa Hamdi Xavier Mariette Véronique Godot Karin Weldingh Abdul Monem Hamid Maria-Victoria Prejean Gabriel Baron Marc Lemann Xavier Puechal Maxime Breban Francis Berenbaum Jean-Charles Delchier René-Marc Flipo Bertrand Dautzenberg Dominique Salmon Marc Humbert Dominique Emilie |
| Institution: | 1. INSERM UMR-S764, Service d'Hépato-Gastro-Entérologie and Service de Microbiologie-Immunologie Biologique, H?pital Antoine Béclère, Assistance Publique – H?pitaux 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, H?pital 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, H?pital 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, H?pital 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, H?pital A. Paré, AP-HP, 9 avenue Charles-de-Gaulle, 92100, Boulogne, France 9. Service de Rhumatologie, H?pital St. Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France 10. Service de Gastro-entérologie, H?pital H. Mondor, AP-HP, 51 rue du Maréchal de Lattre de Tassigny, 94400, Créteil, France 11. Service de Rhumatologie, H?pital C. Huriez, rue Michel Polonovski, 59037, Créteil, Lille, France 12. Service de Pneumologie, H?pital Pitié-Salpétrière, AP-HP, 83 boulevard de l'H?pital, 75013, Paris, France 13. Service de Médecine interne et maladies infectieuses, H?pital Cochin, 27 rue du Faubourg Saint Jacques, 75014, Paris, France 14. Service de Microbiologie – Immunologie Biologique, H?pital A. Béclère, AP-HP Université Paris-Sud, 157 rue de la Porte-de-Trivaux, 92140, Clamart, France |
| Abstract: | Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-alpha 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)-gamma. 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-alpha treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-gamma-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-gamma 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-gamma 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. |
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