| Abstract: | Lymphocyte homing to normal tissues and recruitment to inflammatory tissue sites are controlled, in part, by the selective expression of chemokines, pro-inflammatory cytokines and mediators, and various adhesion proteins and molecules. In the mouse, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is selectively expressed on endothelium of high endothelial venules in gut and gut-associated lymphoid tissue. By interaction with its integrin ligand, alpha 4 beta 7, lymphocytes presumed to be involved in mucosal immunity are selectively recruited to these intestinal sites. After generating monoclonal antibodies against a murine cell line expressing recombinant human MAdCAM-1, we qualitatively and semiquantitatively assessed MAdCAM-1 expression in human tissue sections from various normal and inflammatory disorders. We found that human MAdCAM-1, as in the mouse, is expressed in a tissue-selective manner. In normal tissues, MAdCAM-1 is constitutively expressed to endothelium of venules of intestinal lamina propria. Interestingly, using computer-assisted morphometric analysis, the proportion of venular endothelium within lamina propria that expresses MAdCAM-1 is increased, compared with normal tissues, at inflammatory foci associated with ulcerative colitis and Crohn's disease. Moreover, for the most part, MAdCAM-1 is not detected in the majority of normal or inflamed extra-intestinal tissues, including those with mucosal surfaces. These results are consistent with a role, as originally defined in the mouse, for human MAdCAM-1 in the localization of alpha 4 beta 7+ lymphocytes in the gastrointestinal tract and associated lymphoid tissue. As such, the pathway defined by MAdCAM-1/alpha 4 beta 7 may be a relevant tissue-specific therapeutic target for the modulation of inflammatory bowel disease activity. |
