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
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.
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.
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.
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.