title: Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14⁺ macrophages.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Raja
authors.initials: R
authors.lastname: Atreya
authors.forename: Michael
authors.initials: M
authors.lastname: Zimmer
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bartsch
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Waldner
authors.forename: Imke
authors.initials: I
authors.lastname: Atreya
authors.forename: Helmut
authors.initials: H
authors.lastname: Neumann
authors.forename: Kai
authors.initials: K
authors.lastname: Hildner
authors.forename: Arthur
authors.initials: A
authors.lastname: Hoffman
authors.forename: Ralf
authors.initials: R
authors.lastname: Kiesslich
authors.forename: Andreas D
authors.initials: AD
authors.lastname: Rink
authors.forename: Tilman T
authors.initials: TT
authors.lastname: Rau
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Hermann
authors.initials: H
authors.lastname: Kessler
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000068879:Adalimumab; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D000068582:Certolizumab Pegol; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology*; D000069285:Infliximab; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D018950:Lipopolysaccharide Receptors; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D000069285:Infliximab; D000068879:Adalimumab; D000068582:Certolizumab Pegol