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OP012 IL-23 is centrally involved in mediating molecular resistance to anti-TNF therapy in Crohn’s disease patients

H. Schmitt1*, U. Billmeier1, W. Dieterich1, T. Rath1, S. Sonnewald2, S. Reid2, S. Hirschmann1, K. Hildner1, M.J. Waldner1, J. Mudter3, A. Hartmann4, R. Grützmann5, C. Neufert1, T. Münster6, M.F. Neurath1, R. Atreya1

1Friedrich-Alexander-University Erlangen-Nürnberg, First Department of Medicine, Erlangen, Germany, 2Friedrich-Alexander-University Erlangen-Nürnberg, Department of Biology, Erlangen, Germany, 3Sana Kliniken Ostholstein, Eutin, Germany, 4Friedrich-Alexander-University Erlangen-Nürnberg, Deparment of Pathology, Erlangen, Germany, 5Friedrich-Alexander-University Erlangen-Nürnberg, Department of Surgery, Erlangen, Germany, 6Friedrich-Alexander-University Erlangen-Nürnberg, Department of Anesthesiology, Erlangen, Germany

Background

Anti-tumour necrosis factor (TNF) antibodies are effectively used for treatment in many Crohn’s disease patients. Nevertheless, a relevant subgroup of patients does not respond to anti-TNF therapy. Here we characterised underlying molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.

Methods

Mucosal and blood cells were isolated from 197 Crohn’s disease patients 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

Crohn’s disease patients responding to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on mucosal T cells than non-responders prior to the initiation anti-TNF therapy. We performed an array analysis regarding the differentiated gene regulation profiles in intestinal biopsies of endoscopic non-responders compared with responders during ongoing anti-TNF therapy in CD patients. Within the cohort of CD susceptible genes, there was a significant upregulation of genes that are associated with IL23R-dependent signalling pathways in anti-TNF non-responders compared with responders. Apoptosis--resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders and expressed the gut tropic integrins α4β7. These cells 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 compared with 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. There was no accumulation of CD4+TNFR2+ T cells which were negative for IL23R. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.

Conclusion

Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn’s disease. IL-23 is centrally involved in mediating resistance to anti-TNF therapy in Crohn’s disease patients and thereby represents a suitable molecular target in Crohn’s disease patients refractory to anti-TNF therapy.