期刊
GUT
卷 68, 期 5, 页码 814-828出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2017-315671
关键词
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资金
- Deutsche Forschungsgemeinschaft [CRC1181, KFO257]
- International Organization for the Study of Inflammatory Bowel Diseases
- Emerging Fields Initiative of the University Erlangen-Nurnberg
- Deutsche Forschungsgemeinschaft
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 a4 ss 7, and exhibited increased expression of IFN-., T-bet, IL-17A and ROR.t compared with TNFR2+ IL23R-cells, indicating a mixed Th1/Th17like 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 E xpansion 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.
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