Details

Autor(en) / Beteiligte

• Atreya, Raja
• Zimmer, Michael
• Bartsch, Brigitte
• Waldner, Maximilian J
• Atreya, Imke
• Neumann, Helmut
• Hildner, Kai
• Hoffman, Arthur
• Kiesslich, Ralf
• Rink, Andreas D
• Rau, Tilman T
• Rose–John, Stefan
• Kessler, Hermann
• Schmidt, Jan
• Neurath, Markus F

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

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2011-12, Vol.141 (6), p.2026-2038

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2011

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.