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

Schmitt H, Billmeier U, Dieterich W, Rath T, Sonnewald S, Reid S, Hirschmann S, Hildner K, Waldner M, Mudter J, Hartmann A, Grützmann R, Neufert C, Münster T, Neurath M, Atreya R (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Gut BMJ Publishing Group

DOI: 10.1136/gutjnl-2017-315671

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 with CRIS profile

Heike Knott Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Walburga Dieterich Medizinische Fakultät Sophia Sonnewald Department Biologie Stephen Reid Lehrstuhl für Biochemie Kai Hildner Juniorprofessur für Pneumologie/ Immunologie Maximilian Waldner Lehrstuhl für Innere Medizin I Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Robert Grützmann Department of Surgery Clemens Neufert Medizinische Fakultät Tino Münster Department of Anaesthesiology Markus Neurath Lehrstuhl für Innere Medizin I Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur)

Involved external institutions

Sana Kliniken Ostholstein DE Germany (DE)

How to cite

APA:

Schmitt, H., Billmeier, U., Dieterich, W., Rath, T., Sonnewald, S., Reid, S.,... Atreya, R. (2018). Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease. Gut. https://dx.doi.org/10.1136/gutjnl-2017-315671

MLA:

Schmitt, Heike, et al. "Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease." Gut (2018).

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