Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases

• Published in: World journal of gastroenterology : WJG Vol. 22; no. 42; pp. 9300 - 9313
• Main Authors: Billmeier, Ulrike, Dieterich, Walburga, Neurath, Markus F, Atreya, Raja
• Format: Journal Article
• Language: English
• Published: United States Baishideng Publishing Group Inc 14.11.2016
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Antibodies - therapeutic use; Antibody-Dependent Cell Cytotoxicity - drug effects; Apoptosis - drug effects; Colitis, Ulcerative - diagnosis; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - immunology; Colitis, Ulcerative - metabolism; Crohn Disease - diagnosis; Crohn Disease - drug therapy; Crohn Disease - immunology; Crohn Disease - metabolism; Gastrointestinal Agents - therapeutic use; Humans; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - immunology; Inflammation Mediators - metabolism; Intestines - drug effects; Intestines - immunology; Intestines - metabolism; Intestines - pathology; Review; Signal Transduction - drug effects; Treatment Outcome; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Transmembrane tumor necrosis factor; Mucosal immunology; Lamina propria mononuclear cells; Apoptosis; Crohn’s disease; Ulcerative colitis
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v22.i42.9300

Anti-tumor necrosis factor(TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases(IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn’s disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each antiTNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membranebound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with antiTNF antibodies in chronic intestinal inflammation, by predicting response to therapy.