Article Text

Immune response profiling of patients with spondyloarthritis reveals signalling networks mediating TNF-blocker function in vivo
  1. Silvia Menegatti1,2,3,
  2. Vincent Guillemot4,
  3. Eleonora Latis1,2,
  4. Hanane Yahia-Cherbal1,2,
  5. Daniela Mittermüller1,
  6. Vincent Rouilly5,
  7. Elena Mascia1,
  8. Nicolas Rosine1,2,
  9. Surya Koturan1,2,
  10. Gael A Millot4,
  11. Claire Leloup1,
  12. Darragh Duffy6,
  13. Aude Gleizes7,8,
  14. Salima Hacein-Bey-Abina7,8,
  15. Milieu Intérieur Consortium,
  16. Jérémie Sellam9,10,
  17. Francis Berenbaum9,10,
  18. Corinne Miceli-Richard1,11,12,
  19. Maxime Dougados11,12,13,
  20. Elisabetta Bianchi1,12,
  21. Lars Rogge1,12
    1. 1 Immunoregulation Unit, Department of Immunology, Institut Pasteur, Paris, France
    2. 2 Université Paris Diderot, Sorbonne Paris Cité, Paris, France
    3. 3 INSERM U932, Institut Curie, PSL Research University, Paris, France
    4. 4 Bioinformatics and Biostatistics Hub—Département de Biologie Computationelle, Institut Pasteur, USR 3756 IP CNRS, Paris, France
    5. 5 DATACTIX, Paris, France
    6. 6 Institut Pasteur, Translational Immunology Laboratory, Department of Immunology, Paris, France
    7. 7 Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, AP-HP, Le-Kremlin-Bicêtre, France
    8. 8 UTCBS CNRS UMR 8258, INSERM U1267, Faculté de Pharmacie de Paris, Université de Paris, Paris, France
    9. 9 Sorbonne Université, Service de Rhumatologie, Hôpital Saint-Antoine, AP-HP, Paris, France
    10. 10 Centre de Recherche Saint-Antoine, INSERM UMR_S 938, Paris, France
    11. 11 Paris Descartes University, Rheumatology Department, Cochin Hospital, AP-HP, Paris, France
    12. 12 Unité Mixte AP-HP/Institut Pasteur, Institut Pasteur, Paris, France
    13. 13 INSERM U1153 Clinical Epidemiology and Biostatistics, PRES Sorbonne Paris-Cité, Paris, France
    1. Correspondence to Dr Lars Rogge, Department of Immunology, Institut Pasteur, 75724 Paris, Île-de-France, France; lars.rogge{at}pasteur.fr

    Abstract

    Objectives Antitumour necrosis factor (TNF) therapy has revolutionised treatment of several chronic inflammatory diseases, including spondyloarthritis (SpA). However, TNF inhibitors (TNFi) are not effective in all patients and the biological basis for treatment failure remains unknown. We have analysed induced immune responses to define the mechanism of action of TNF blockers in SpA and to identify immunological correlates of responsiveness to TNFi.

    Methods Immune responses to microbial and pathway-specific stimuli were analysed in peripheral blood samples from 80 patients with axial SpA before and after TNFi treatment, using highly standardised whole-blood stimulation assays. Cytokines and chemokines were measured in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, and gene expression was monitored using nCounter assays.

    Results Anti-TNF therapy induced profound changes in patients’ innate immune responses. TNFi action was selective, and had only minor effects on Th1/Th17 immunity. Modular transcriptional repertoire analysis identified prostaglandin E2 synthesis and signalling, leucocyte recirculation, macrophage polarisation, dectin and interleukin (IL)-1 signalling, as well as the nuclear factor kappa B (NF-kB) transcription factor family as key pathways targeted by TNF blockers in vivo. Analysis of induced immune responses before treatment initiation revealed that expression of molecules associated with leucocyte adhesion and invasion, chemotaxis and IL-1 signalling are correlated with therapeutic responses to anti-TNF.

    Conclusions We show that TNFi target multiple immune cell pathways that cooperate to resolve inflammation. We propose that immune response profiling provides new insight into the biology of TNF-blocker action in patients and can identify signalling pathways associated with therapeutic responses to biological therapies.

    • spondylitis
    • ankylosing
    • tumor necrosis factor inhibitors
    • biological therapy
    • immune system diseases
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    Footnotes

    • Handling editor Josef S Smolen

    • Twitter @skoturan, @larhumato

    • Correction notice This article has been corrected since it published Online First. The author's name has been corrected for Dr Millot and Prof Micelli-Richard.

    • Collaborators Milieu Intérieur Consortium: Laurent Abel; Andres Alcover; Hugues Aschard; Kalla Astrom; Philippe Bousso; Pierre Bruhns; Ana Cumano; Caroline Demangel; Ludovic Deriano; James Di Santo; Françoise Dromer; Gérard Eberl; Jost Enninga, Jacques Fellay; Ivo Gomperts-Boneca; Milena Hasan; Serge Hercberg; Olivier Lantz; Hugo Mouquet; Etienne Patin; Sandra Pellegrini; Stanislas Pol; Antonio Rausell; Lars Rogge; Anavaj Sakuntabhai; Olivier Schwartz; Benno Schwikowski; Spencer Shorte; Frédéric Tangy; Antoine Toubert; Mathilde Trouvier; Marie-Noëlle Ungeheuer; Darragh Duffy; Matthew L. Albert; Lluis Quintana-Murci.

    • Contributors SM, EB and LR designed the study, analysed data, interpreted results and wrote the manuscript. SM, EL, EM, HY-C, DM, CL, NR and SK performed experiments. AG and SH-B-A analysed drug levels and antidrug antibiodies in serum samples. SM, VG, VR, GM, EB and LR performed bioinformatics data analysis. DD provided data from the Milieu Intérieur cohort. JS and FB provided patient samples and clinical data. CM and MD had overall medical oversight, provided patient samples and clinical data, performed clinical data analysis and revised the manuscript. All authors approved the manuscript.

    • Funding SM was a scholar of the Pasteur-Paris University (PPU) International PhD programme and supported by a grant from the Fondation pour la Recherche Médicale. EL was supported by a fellowship from the Université Paris Diderot. This study was supported by grants from Institut Pasteur, the French Government’s Investissement d’Avenir Programme, Laboratoire d’Excellence “Milieu Intérieur” (ANR-10-LABX-69-01), FOREUM Foundation for Research in Rheumatology, the Fondation Arthritis, MSD Avenir (Project iCARE-SpA), a Bourse Passerelle from Pfizer and a Sanofi Innovation Award Europe.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval This study fulfils the current Good Clinical Practice Guidelines and a clinical protocol has been accepted by regulatory committees: Comité de Protection des Personnes Ile de France III; Référence CPP: no AT-100), Institut Pasteur (Projet de recherché clinique no 2011-32, CCTIRS (DGRI CCTIRS MG/CP°2012.035), and CNiL (Décision DR-2013-080).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.