Adhesion Molecules as a Therapeutic Target in IBD

Abstract

Recruitment of circulating leukocytes to areas of inflammation is a key process in the pathophysiology of inflammatory bowel diseases, including ulcerative colitis (UC). This is a finely regulated multistep process in which specialised adhesion and signalling molecules mediate a series of sequential steps. Following activation, integrins expressed on the surface of leukocytes become the key mediators of firm adhesion and emigration through interaction with immunoglobulin superfamily molecules expressed on the vascular endothelium. The anti α4 antibody natalizumab has shown efficacy in inducing and maintaining response and remission in patients with moderate and severe Crohn’s disease. However, a major safety setback involving the onset of progressive multifocal leukoencephalopathy (PML) in 1/1000 treated cases led to limitations on its clinical use and application in UC. The more selective anti α4β7 antibody vedolizumab has proven efficacious for inducing clinical and endoscopic remission in UC. Selective expression of the α4β7 receptor MAdCAM-1, which occurs predominantly in the intestine, may avoid the risk of those central nervous system infectious complications associated with the nonselective blockade of all α4 integrins. Moreover, treatment with anti-MAdCAM-1 or anti-α7 antibody (etrolizumab) showed promising results for inducing remission in UC. In conclusion, the development of safe and effective drugs that target these molecular components of the inflammatory response may yield novel, improved therapies for inflammatory bowel disease (IBD) that address as yet unmet needs.