INHIBITION OF INSULITIS AND PREVENTION OF DIABETES IN NONOBESE DIABETIC MICE BY BLOCKING L-SELECTIN AND VERY LATE ANTIGEN-4 ADHESION RECEPTORS

Leukocyte adhesion to the endothelial venules in the pancreatic islets is thought to be one of the initial steps in the development of insul in-dependent diabetes mellitus. It has been suggested that leukocyte a dhesion to endothelium is a sequential multistep process involving var ious different homing receptors. We report here that blocking differen t homing receptors-namely, L-selectin and very late antigen 4 (VLA-4)- which function during different stages of the adhesion process, by spe cific monoclonal antibodies inhibits insulitis and prevents diabetes i n mice. Moreover, leukocyte attachment to the inflamed vessels within pancreatic sections could be inhibited by anti-L-selectin and anti-VLA -4 antibodies. Interestingly, anti-L-selectin or anti-VLA-4 antibody d id not appear to influence the autoimmune response to a panel of pancr eatic beta-cell autoantigens. These data suggest that L-selectin and V LA-4 receptors are involved in mediating leukocyte homing to the islet s and that intervention of these two adhesion pathways may provide a n ovel approach for treatment of autoimmune diseases such as insulin-dep endent diabetes mellitus.