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α4 Integrin blockade in inflammatory bowel disease

Inflammatory bowel disease comprises Crohn’s disease (CD), a Th1 lymphocyte mediated chronic transmural inflammatory disease, and ulcerative colitis, resembling a Th2 lymphocyte mediated mucosal inflammation of the colon. Studies of patients with inflammatory bowel disease show that endothelial cells extracted from inflamed intestinal mucosa demonstrate increased α4 integrin dependent adhesiveness to leucocytes in vitro.1

Integrins form a large family of transmembrane proteins required for cell adhesion, morphogenesis, migration, and differentiation, attach the cell to the extracellular matrix or to other cells, and anchor the cytoskeleton to the plasma membrane. Integrins consist of two non-covalently bound α and β subunits of 120–180 kDa and 90–120 kDa, respectively. The α4 chain contains about 1000 amino acids and in association with the β7 chain defines an integrin subfamily specifically involved in the interaction of lymphocytes with the intestinal mucosa. The α4β7 integrin is widely expressed in the intestine and is present on most lamina propria T cells and IgA secreting B cells. The expression of α4β7 on intraepithelial lymphocytes is lower. The main ligand for α4β7 is mucosal vascular addressin cell adhesion molecule (MADCAM-1), a member of the immunoglobulin superfamily as mentioned below, but other ligands include fibronectin (an extracellular matrix protein), vascular cell adhesion molecule-1 (VCAM-1), and α4 integrin itself. α4 Integrin in the low affinity state, as well as L-selectin play a part in rolling of the lymphocytes in intestinal vascular epithelium, interacting with a number of ligands, including MADCAM-1. Activating signals to the lymphocytes, such as …