title: Mechanism of Action of Anti-TNF Therapy in Inflammatory Bowel Disease.
abstract: Several anti-tumour necrosis factor [TNF] blocking strategies have been evaluated in patients with Crohn's disease. Compounds that have been tested included the full monoclonal IgG1 antibodies infliximab and adalimumab, the pegylated anti-TNF F[ab']2 fragment certolizumab, an IgG4 anti-TNF CDP571 with reduced affinity for the Fc receptor, the soluble TNF receptor I onercept, and the TNF receptor II-Fc fusion protein etanercept. The endpoints of these studies suggest that not all methods of blocking TNF are equal. Here we will review the differences in the clinical, biochemical, and endoscopic endpoints of the major clinical studies. Collectively the data suggest that only IgG1 monoclonal antibodies have the ability to induce complete clinical, biochemical, and endoscopic remission. We discuss the potential multiple modes of action that may contribute to the response to full IgG1 anti-TNFs, focusing on the rapid induction of lamina propria T cell apoptosis and Fc receptor-dependent induction of M2-type wound-healing macrophages. We discuss how novel insights into the mechanism of action of anti-TNFs in Crohn's disease may contribute to the development of novel anti-TNFs with improved efficacy.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Alon D
authors.initials: AD
authors.lastname: Levin
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Manon E
authors.initials: ME
authors.lastname: Wildenberg
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands g.r.vandenbrink@amc.nl.
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
mesh_terms: D000068879:Adalimumab / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D000068582:Certolizumab Pegol / Q000494:pharmacology* / Q000627:therapeutic use; D016099:Endoscopy, Gastrointestinal; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000069285:Infliximab / Q000494:pharmacology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068582:Certolizumab Pegol
keywords: Crohn’s; T cell; adalimumab; anti-TNF; apoptosis; certolizumab; infliximab; macrophage; mucosal healing; wound healing