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Together with immunosuppressants, anti-tumour necrosis factor (TNF) monoclonal antibodies represent a major class of treatment for the inflammatory bowel diseases (IBD) therapeutic arsenal. Almost 20 years after the first report of infliximab in Crohn's disease,1 we do not know exactly how these TNF inhibitors control the inflammatory response, and their mechanism of action is still a matter of investigation.
Werner et al2 show that infliximab and adalimumab not only induce T-cell apoptosis but also inhibit T-cell function, activation and cycling (see page 1016). They demonstrate that while T-cell apoptosis is mediated by TNF signalling, the inhibition of T-cell activation and cycling is not dependent on TNF signalling but on Notch-1 signalling. They thereby provide new insights on the mechanisms of action of TNF inhibitors, and more specifically on T cells.
Anti-TNF monoclonal antibodies bind and neutralise TNF, and downregulate the inflammatory response, through suppression of pro-inflammatory cytokine secretion, inhibition of chemokine secretion and downregulation of adhesion molecules. These effects can be mediated by direct neutralisation of soluble TNF and interaction with membrane-bound TNF. Furthermore, TNF inhibitors clearly participate in the elimination and clearance of active inflammatory cells from inflamed tissue. This can be achieved by a number of mechanisms including apoptosis induction, antibody and complement-mediated cytotoxicity and inhibition of cell migration into the intestinal tissue. Many leucocyte and endothelial adhesion molecules as well as leucocyte chemokine receptors and endothelial chemokines are upregulated in the inflamed mucosa of IBD patients. It was recently shown that most of these molecules are downregulated in infliximab responders.3
It is clear that anti-TNF agents can induce the apoptosis of active inflammatory cells. In vitro, both infliximab and adalimumab induce …
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