The roles of alpha 4-integrins in the development of insulin-dependent diabetes mellitus.

Lymphocyte/endothelial adhesion followed by transendothelial migration is a key event in the development of organ-specific autoimmunity. Selective interactions of cell surface AM regulate lymphocyte migration under normal as well as pathologic inflammatory conditions. NOD mice are an ideal model for investigating the roles of AM in regulation of lymphocyte migration to target organs in autoimmune diseases such as IDDM. Both in vitro and in vivo studies in NOD mice strongly suggest that the mucosal (alpha 4 beta 7/MAdCAM-1) adhesion system and alpha 4-integrin/VCAM-1 appear to be prominent pathways for insulitis development. In contrast, alpha 4-mediated interactions in NOD inflamed salivary and lacrimal gland and in the inflamed CNS of rodents with EAE seem to be dominated by alpha 4-integrins and VCAM-1. The fact that blocking alpha 4-integrin pathways in NOD mice leads to successful interruption of the diabetogenic process suggests that AM provide a potential therapeutic target for human IDDM. Further studies on IDDM patients will prove helpful for understanding IDDM pathogenesis and in providing a basis for designing AM-based therapeutic approaches.