title: Impact of anti-TNF therapy on NK cells function and on immunosurveillance against B-cell lymphomas.
abstract: OBJECTIVE
  Rheumatoid arthritis (RA) is associated with an increased risk of lymphoma linked to activity of the disease. Immunosuppressive drugs have been suspected to induce an additional risk. Since, NK cells have been recently shown to participate to anti-lymphoma immunosurveillance, we aimed to assess if anti-TNF might impact their anti-lymphoma activity.
  
  
  METHODS
  NK cells have been assessed ex vivo in patients with RA treated with methotrexate (MTX) with or without anti-TNF. Phenotype has been studied by flow cytometry and function has been assessed after NKp30-cross linking. NK have been cultured 6 days in presence of anti-TNF, TNF-R inhibitors or controls and phenotype has been studied. Then cytotoxicity against 2 B non-Hodgkin lymphoma cell lines [Farage (EBV+) and SU-DHL4 (EBV-)] was assessed.
  
  
  RESULTS
  Exposure to anti-TNF was associated with a decreased activation of NK cells. NK cells exhibited an impaired function in patients treated with anti-TNF compared to patients treated with MTX alone as assessed by the percentage of degranulation (20.9% [18.5-32.9] vs 31.3% [21.5-49.1], p = 0.04) and a decreased IFN-γ secretion ((17.4% [8.9-25.9] vs to 29.7% [22.5-43.1], p = 0.007). In vitro, exposure to anti-TNF impaired NK cells function and impacted negatively anti-lymphoma activity. These effects may be the consequence of inhibition of TNFR1 signaling.
  
  
  CONCLUSIONS
  Thus, even if meta-analysis of randomized controlled trials and of registries have not demonstrated to date an increased risk of lymphoma with anti-TNF, cautious must be pursued concerning this possible side effect in patients with long-term anti-TNF exposure.
authors.affiliation: INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France; Department of Rheumatology, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France. Electronic address: gaetane.nocturne@aphp.fr.
authors.forename: Gaetane
authors.initials: G
authors.lastname: Nocturne
authors.affiliation: INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Saida
authors.initials: S
authors.lastname: Boudaoud
authors.affiliation: INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Bineta
authors.initials: B
authors.lastname: Ly
authors.affiliation: INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Pascaud
authors.affiliation: INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Paoletti
authors.affiliation: INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud, Le Kremlin-Bicêtre, France; Department of Rheumatology, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000276:immunology / Q000628:therapy*; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000453:epidemiology / Q000276:immunology*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D008727:Methotrexate
keywords: Anti-TNF; Auto-immunity; Lymphoma; NK cells