Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease.

Abstract

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.

• Authors: Heike Schmitt, Ulrike Billmeier, Walburga Dieterich, Timo Rath, Sophia Sonnewald, Stephen Reid, Simon Hirschmann, Kai Hildner, Maximilian J Waldner, Jonas Mudter, Arndt Hartmann, Robert Grützmann, Clemens Neufert, Tino Münster, Markus F Neurath, Raja Atreya
• Journal: Gut (Gut) Vol. 68 Issue 5 Pg. 814-828 (05 2019) ISSN: 1468-3288 [Electronic] England
• PMID: 29848778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chemical References

• Gastrointestinal Agents
• IL17A protein, human
• IL23R protein, human
• Interleukin-17
• Receptors, Interleukin
• Receptors, Tumor Necrosis Factor, Type II
• Infliximab
• Adalimumab

Topics

• Adalimumab (therapeutic use)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Crohn Disease (drug therapy, metabolism, pathology)
• Drug Resistance
• Gastrointestinal Agents (therapeutic use)
• Humans
• Infliximab (therapeutic use)
• Interleukin-17 (metabolism)
• Intestinal Mucosa (metabolism, pathology)
• Male
• Middle Aged
• Receptors, Interleukin (metabolism)
• Receptors, Tumor Necrosis Factor, Type II (metabolism)
• T-Lymphocytes (physiology)
• Young Adult