Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ …
R Atreya, M Zimmer, B Bartsch, MJ Waldner, I Atreya… - Gastroenterology, 2011 - Elsevier
R Atreya, M Zimmer, B Bartsch, MJ Waldner, I Atreya, H Neumann, K Hildner, A Hoffman…
Gastroenterology, 2011•ElsevierBACKGROUND & 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 …
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 …
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.
Elsevier