MAdCAM mediates lymphocyte-endothelial cell adhesion in a murine model of chronic colitis

Previous studies have revealed that the expression of several endothelial c ell adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1), v ascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhes ion molecule 1 (MAdCAM-1)] is dramatically elevated in the chronically infl amed colonic vasculature of severe combined immunodeficient (SCID) mice rec onstituted with congenic CD4=, CD45RB(high) T lymphocytes. The objective of this study was to define the contribution of different endothelial cell ad hesion molecules to the lymphocyte-endothelial cell (L/E) adhesion observed in the colonic microvasculature in this experimental model of inflammatory bowel disease. Fluorescently labeled T lymphocytes, isolated from spleens of normal BALB/C mice, were injected intravenously into SCID mice that had been reconstituted with CD4+, CD45RB(high) T lymphocytes either before (3 w k after reconstitution) or after (7 wk postreconstitution) the onset of cli nical signs of colitis (i.e., diarrhea, loss of body wt). Intravital fluore scence microscopy was used to quantify L/E adhesion in different-sized venu les of the colonic submucosa during the development of colitis. L/E adhesio n was noted in some segments of the vasculature in precolitic SCID mice (3 wk after reconstitution) but not in similar-sized vessels of control (wild type and SCID) mice. L/E adhesion was observed in a greater proportion of v enules and occurred with greater intensity in the mucosa of colitic mice (7 wk postreconstitution). Pretreatment with a blocking monoclonal antibody a gainst MAdCAM-1, but not ICAM-1 or VCAM-1, significantly and profoundly red uced L/E adhesion in colitic mice. Immunohistochemical staining also reveal ed the localization of T cells on colonic endothelial cells expressing MAdC AM-1. These findings indicate that MAdCAM-1 is largely responsible for recr uiting T lymphocytes into inflamed colonic tissue.