A PREDOMINANT ROLE OF INTEGRIN ALPHA(4) IN THE SPONTANEOUS DEVELOPMENT OF AUTOIMMUNE DIABETES IN NONOBESE DIABETIC MICE

To elucidate the role of cell adhesion molecules in the pathogenesis o f insulin-dependent diabetes mellitus and to determine the predominant lymphocytic homing pathway(s) involved in the selective lymphocytic i nfiltration of pancreatic islets (insulitis), nonobese diabetic mice w ere treated with monoclonal antibodies specific for the L-selectin and integrin alpha(4) lymphocyte adhesion molecules. Treatment of neonata l mice with either anti-L-selectin or anti-integrin alpha(4) monoclona l antibodies for the first 4 weeks of life led to a significant and lo ng-term protection against spontaneous occurrence of insulitis and dia betes. The same treatment failed to inhibit lymphocytic infiltration o f the salivary glands (sialadenitis). This tissue-specific inhibition of inflammation may be attributed to differences between the pancreas and salivary gland in their expression of endothelial ligands for L-se lectin (peripheral vascular addressin) and for integrin alpha(4) (muco sal addressin cell adhesion molecule 1 and vascular cell adhesion mole cule 1). Mucosal addressin cell adhesion molecule 1 is highly expresse d by vessels within the inflamed islets but was not detected in the sa livary glands, In contrast, peripheral vascular addressin- and vascula r cell adhesion molecule 1-expressing vessels can be found in almost e very area of inflammation within the salivary glands but are seen in o nly 40-50% of inflamed islets. Anti-L-selectin and anti-integrin alpha (4) treatment had no demonstrable effect on anti-beta-cell autoimmunit y or on the immune responses to foreign antigens. Therapeutic treatmen t with anti-L-selectin after the onset of insulitis from 10 to 14 week s of age delayed the onset but failed to prevent spontaneous insulin-d ependent diabetes mellitus, whereas anti-integrin alpha(4) treatment r esulted in a significant and long-lasting suppression of the disease. These data strongly suggest that integrin alpha(4) plays a prominent r ole in the spontaneous development of insulitis and diabetes in nonobe se diabetic mice.