Amelioration of Murine Experimental Colitis by Inhibition of Mucosal Addressin Cell Adhesion Molecule-11

Abstract

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is an adhesion molecule that mediates recruitment of lymphocytes into the gut mucosa. Attenuation of excessive expression of MAdCAM-1 in the inflamed mucosa could be useful for treatment of inflammatory bowel diseases. The aim of this study was to investigate whether anti-MAdCAM-1 antibody has a prophylactic effect on experimental colitis induced by dextran sulfate sodium (DSS). Colitis was induced by orally feeding BALB/c mice 5% DSS (mol. wt. 5000). Mice were sacrificed at intervals up to 21 days after administration to evaluate the changes over time in intestinal damage. The infiltrating lymphocytes and their subpopulations, and the expression of cell adhesion molecules were determined by immunohistochemistry. In another set of experiments, the attenuating effect of i.p.-injected anti-MAdCAM-1 antibody on colonic lesions was evaluated on day 14. Significant histological damage with shortening of crypts was observed on day 14 in colonic mucosa of DSS-treated mice. Before mucosal inflammation had become significant, expression of MAdCAM-1 was already increased in the microvessels of lamina propria on day 7. Significant infiltration of β7-integrin-positive T and B cells in the mucosa was then noted on day 14. Administration of anti-MAdCAM-1 antibody significantly reduced colonic injury as well as the infiltration of β7-integrin-positive lymphocytes in the colonic mucosa. This antibody also was effective when given 7 days after the start of DSS treatment. In the present study, we demonstrated that anti-MAdCAM-1 antibody significantly ameliorates DSS-induced colitis, suggesting that MAdCAM-1 may be useful for control of inflammatory bowel diseases.