title: Inhibition of anti-tuberculosis T-lymphocyte function with tumour necrosis factor antagonists.
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.
authors.affiliation: INSERM UMR-S764, Service d'Hépato-Gastro-Entérologie, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Institut Paris-Sud sur les Cytokines, Université Paris-Sud, INSERM U764, 32 rue des Carnets, 92140, Clamart, France.
authors.forename: Haïfa
authors.initials: H
authors.lastname: Hamdi
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.forename: Véronique
authors.initials: V
authors.lastname: Godot
authors.forename: Karin
authors.initials: K
authors.lastname: Weldingh
authors.forename: Abdul Monem
authors.initials: AM
authors.lastname: Hamid
authors.forename: Maria-Victoria
authors.initials: MV
authors.lastname: Prejean
authors.forename: Gabriel
authors.initials: G
authors.lastname: Baron
authors.forename: Marc
authors.initials: M
authors.lastname: Lemann
authors.forename: Xavier
authors.initials: X
authors.lastname: Puechal
authors.forename: Maxime
authors.initials: M
authors.lastname: Breban
authors.forename: Francis
authors.initials: F
authors.lastname: Berenbaum
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Delchier
authors.forename: René-Marc
authors.initials: RM
authors.lastname: Flipo
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dautzenberg
authors.forename: Dominique
authors.initials: D
authors.lastname: Salmon
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
mesh_terms: D000068879:Adalimumab; D000907:Antibodies, Bacterial / Q000096:biosynthesis* / Q000187:drug effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000942:Antigens, Bacterial / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D003424:Crohn Disease / Q000150:complications / Q000276:immunology; D004334:Drug Administration Schedule; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology*; D000069285:Infliximab; D008213:Lymphocyte Activation / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D025242:Spondylarthropathies / Q000150:complications / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D014373:Tuberculin / Q000276:immunology; D014376:Tuberculosis / Q000150:complications; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C117940:CFP-10 protein, Mycobacterium tuberculosis; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept