Objective Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn’s disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.
Design Mucosal and blood cells were isolated from patients with Crohn’s disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS.
Results Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R− cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.
Conclusions Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn’s disease refractory to anti-TNF therapy.
- crohn’s disease
- intestinal T cells
- mucosal immunology
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Statistics from Altmetric.com
RA and MFN share senior authorship.
Contributors HS, UB, WD, TR, SS, SR, SH, KH, MJW, JM, AH, RG, CN, TM, MFN and RA provided reagents, protocols, samples or designed experiments; HS, UB and WD performed experiments; HS, UB, MFN and RA designed the study, analysed, discussed, interpreted data and wrote the manuscript; MFN and RA directed the work.
Funding This study was supported by the Deutsche Forschungsgemeinschaft (CRC1181 Project C02) to HS, CN and RA; KFO257 to MFN and RA, by a research operating grant from the International Organization for the Study of Inflammatory Bowel Diseases to MFN and RA, and by the Emerging Fields Initiative of the University Erlangen-Nürnberg to MFN and RA. The Heisenberg Professorship of RA is funded by the Deutsche Forschungsgemeinschaft.
Competing interests MFN provided expert scientific advice or received funding from the following companies: Boehringer, Giuliani Pharma, PPD, Sterna, Janssen, Schering-Plough, Essex, UCB, Abbott, Abbvie, Falk, Pentax. RA provided expert scientific advice or received funding from the following companies: Abbvie, Janssen.
Patient consent Not required.
Ethics approval Ethical Review Committee of the Friedrich-Alexander-University Erlangen-Nürnberg, Germany.
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it published Online First. The shared senior authorship statement has been added.
Presented at Part of this work was presented at Digestive Disease Week (DDW) in Chicago (2017), United European Gastroenterology Week in Barcelona (2017) and Congress of European Crohn’s and Colitis Organisation (ECCO) in Vienna (2018).
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.