CELL-ADHESION MOLECULES - A SELECTIVE THERAPEUTIC TARGET FOR ALLEVIATION OF IDDM

Selective homing of autoreactive lymphocytes to the pancreatic islets of Langerhans is essential for triggering the cascade of molecular and cellular interactions which culminate in the specific destruction of the insulin-producing beta-cells. Based upon the sequential multistep model of lymphocyte adhesion to the endothelium, we investigated the p ossibility of preventing the progression of insulin-dependent diabetes mellitus (IDDM) by selectively blocking L-selectin and alpha 4-integr in homing receptors, which function at different stages of the adhesio n process. Treatment of NOD mice with mAb specific for L-selectin or a lpha 4-integrin resulted in a significant inhibition of lymphocytic in filtration (insulitis). Both spontaneous development and acute transfe r of IDDM were completely prevented by administration of anti-alpha 4- integrin antibody and partially inhibited by anti-L-selectin antibody. The protective effect was of long duration. Interestingly, the autoim mune T cell responses to a panel of beta cell autoantigens and the lym phocytic infiltration of salivary glands (sialadenitis) appeared unaff ected by anti-L-selectin or anti-alpha 4-integrin treatment, These dat a suggest that prevention of lymphocyte homing to the pancreatic islet s may provide a selective target for prevention/treatment of IDDM in p atients.