ADMINISTRATION OF MONOCLONAL-ANTIBODIES AGAINST VASCULAR CELL-ADHESION MOLECULE-1 VERY LATE ANTIGEN-4 ABROGATES PREDISPOSING AUTOIMMUNE DIABETES IN NOD MICE

The interaction of vascular cell adhesion molecule-1 and very late ant igen-4 (alpha 4 beta 1-integrin) has been recently known to be profoun dly involved in the trafficking of lymphocytes from the circulation in to the inflammatory tissues. To elucidate the role of these molecules in the development of autoimmune diabetes, the expression of these adh esion molecules on inflamed islets and the effects of administration o f monoclonal antibodies to these molecules on insulitis and overt diab etes were evaluated in nonobese diabetic (NOD) mice. Immunohistochemic al study revealed the overexpression of vascular cell adhesion molecul e-1 on vascular endothelium near or within inflamed islets and alpha 4 -integrin on islet-infiltrating mononuclear cells. Either anti-vascula r cell adhesion molecule-1 or anti-alpha 4-integrin monoclonal antibod y prevented the transfer of diabetes in irradiated NOD mice which rece ived spleen cells from acutely diabetic NOD mice. When both monoclonal antibodies were administrated to NOD mice during 2-30 weeks of age, n either lymphocytic infiltration to islets nor overt diabetes was obser ved. Furthermore, administration of these antibodies even from 10 week s of age could inhibit the development of insulitis and diabetes, wher eas administration during 2-5 weeks of age could not. Splenocytes obta ined from these treated mice showed no significant change of cytokine production and preserved the ability to transfer diabetes into NOD sci d/scid mice. This suggests that treatment with antibodies against thes e adhesion molecules can inhibit insulitis and diabetes without affect ing the Th1/Th2 balance or effector T cells. The blockade of vascular cell adhesion molecule-1/very late antigen-4 interaction would be suit able for therapeutical treatment of the predisposing and latent type I (insulin-dependent) diabetic subjects. (C) 1995 Academic Press, Inc.