| Anti-TNF antibodies target T-cell apoptosis in inflammatory bowel diseases via TNFR2 and intestinal CD14+ macrophages. | |
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MedLine Citation:
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PMID: 21875498 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: The anti-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 diseases (IBD). METHODS: CD14+ macrophages and CD4+ T-cells were isolated from peripheral blood and lamina propria mononuclear cells from IBD and control patients. Cell surface markers and apoptosis were assessed by immunohistology and FACS techniques. RESULTS: Lamina propria CD14+ macrophages showed significantly more frequent and higher mTNF expression than CD4+ T-cells in IBD, whereas mTNF-dependent signaling proteins such as TNFR2, TRAF2 and NF-kappaB 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 co-cultured 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 IL-6 signal transduction. Blockade of IL-6R signalling augmented anti-TNF-induced T-cell apoptosis in IBD. CONCLUSION: Clinically effective anti-TNF antibodies are able to induce T-cell apoptosis in IBD only when mucosal TNFR2+ T-cells are co-cultured 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. |
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Authors:
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R Atreya; M Zimmer; B Bartsch; M J Waldner; I Atreya; H Neumann; K Hildner; A Hoffman; R Kiesslich; A D Rink; T T Rau; S Rose-John; H Kessler; J Schmidt; M F Neurath |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-26 |
Journal Detail:
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Title: Gastroenterology Volume: - ISSN: 1528-0012 ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Medical Clinic I, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany; Institute of Molecular Medicine, University of Mainz, Mainz, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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