EC3, a heterodimeric disintegrin from Echis carinatus, inhibits human and murine alpha 4 integrin and attenuates lymphocyte infiltration of langerhans islets in pancreas and salivary glands in nonobese diabetic mice

The venom of Echis carinatus suchoreki contains a monomeric disintegrin ech istatin (Mr 5,500 Da) that strongly inhibits alpha IIb beta 3, alpha v beta 3, and alpha 5 beta 1 integrins and a heterodimeric disintegrin called EC3 (M-r 14,762 Da). At nanomolar concentration, EC3 inhibits adhesion of huma n cell lilies expressing alpha 4 beta 1 and alpha 4 beta 7 to immobilized V CAM-1; it has a lower inhibitory effect on alpha 5 beta 1-mediated cell adh esion. In this study, we demonstrated that EC3, in contrast to echistatin, inhibited binding of monoclonal anti-alpha 4 and anti-alpha 5 antibodies to cells expressing alpha 4 beta 7. In a dose-dependent manner and to the sam e extent, EC3 inhibited adhesion of Jurkat cells and murine splenic lymphoc ytes to immobilized VCAM-1, whereas echistatin was not active. EC3 injected intraperitoneally into nonobese diabetic (NOD mice) suppressed development of insulitis and sialoadenitis, whereas echistatin had no significant effe ct, We propose that the effect of EC3 is mediated, at least, in part, by bl ocking alpha 4 beta 1 and alpha 4 beta 7 on murine lymphocytes. (C) 2000 Ac ademic Press.