Antibodies against Tumor Necrosis Factor (TNF) induce t-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ macrophages

• Verfasst von: Atreya, Raja Narayana [VerfasserIn]
• Verfasst von: Zimmer, Michael [VerfasserIn]
• Verfasst von: Bartsch, Brigitte [VerfasserIn]
• Verfasst von: Waldner, Maximilian J. [VerfasserIn]
• Verfasst von: Atreya, Imke [VerfasserIn]
• Verfasst von: Neumann, Helmut [VerfasserIn]
• Verfasst von: Hildner, Kai [VerfasserIn]
• Verfasst von: Hoffman, Arthur [VerfasserIn]
• Verfasst von: Kiesslich, Ralf [VerfasserIn]
• Verfasst von: Rink, Andreas D. [VerfasserIn]
• Verfasst von: Rau, Tilman T. [VerfasserIn]
• Verfasst von: Rose-John, Stefan [VerfasserIn]
• Verfasst von: Kessler, Hermann [VerfasserIn]
• Verfasst von: Schmidt, Jan [VerfasserIn]
• Verfasst von: Neurath, Markus F. [VerfasserIn]
• Titel: Antibodies against Tumor Necrosis Factor (TNF) induce t-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ macrophages
• Verf.angabe: Raja Atreya, Michael Zimmer, Brigitte Bartsch, Maximilian J. Waldner, Imke Atreya, Helmut Neumann, Kai Hildner, Arthur Hoffman, Ralf Kiesslich, Andreas D. Rink, Tilman T. Rau, Stefan Rose-John, Hermann Kessler, Jan Schmidt, and Markus F. Neurath
• E-Jahr: 2011
• Jahr: 27 August 2011
• Umfang: 13 S.
• Fussnoten: Gesehen am 24.03.2022 ; Im Titel ist das Zeichen + hochgestellt
• Titel Quelle: Enthalten in: Gastroenterology
• Ort Quelle: Stanford, Calif. : HighWire Press, 1965
• Jahr Quelle: 2011
• Band/Heft Quelle: 141(2011), 6, Seite 2026-2038
• ISSN Quelle: 1528-0012
• DOI: doi:10.1053/j.gastro.2011.08.032
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Apoptosis Induction
• Sach-SW: Crohn's Disease
• Sach-SW: IL-6
• Sach-SW: mTNF
• K10plus-PPN: 1796547581

Abstract

Background & Aims - The anti-tumor necrosis factor (TNF) antibodies infliximab, adalimumab, and certolizumab pegol have proven clinical efficacy in Crohn's disease. Here, we assessed the effects of anti-TNF antibodies on apoptosis in inflammatory bowel disease (IBD). - Methods - CD14+ macrophages and CD4+ T cells were isolated from peripheral blood and lamina propria mononuclear cells from patients with IBD and control patients. Cell surface markers and apoptosis were assessed by immunohistology and fluorescence-activated cell sorting techniques. - Results - Lamina propria CD14+ macrophages showed significantly more frequent and higher membrane-bound TNF (mTNF) expression than CD4+ T cells in IBD, whereas mTNF-dependent signaling proteins such as TNF receptor (TNFR) 2, TNFR-associated factor (TRAF) 2, and nuclear factor κB were induced in IBD mucosal CD4+ T cells. Most anti-TNF antibodies did not induce T-cell apoptosis in purified peripheral or mucosal CD4+ T cells. However, in contrast to etanercept, administration of all clinically effective anti-TNF antibodies resulted in a significant induction of T-cell apoptosis in IBD when lamina propria CD4+ T cells expressing TNFR2+ were cocultured with mTNF+ CD14+ intestinal macrophages. In contrast, no effects in control patients were noted. T-cell apoptosis in IBD occurred in vivo after treatment with adalimumab and infliximab, was critically dependent on TNFR2 signaling, and could be prevented via interleukin-6 signal transduction. Blockade of interleukin-6R signaling augmented anti-TNF-induced T-cell apoptosis in IBD. - Conclusions - Clinically effective anti-TNF antibodies are able to induce T-cell apoptosis in IBD only when mucosal TNFR2+ T cells are cocultured with mTNF-expressing CD14+ macrophages. The finding that anti-TNF antibodies induce apoptosis indirectly by targeting the mTNF/TNFR2 pathway may have important implications for the development of new therapeutic strategies in IBD.