EC3, a heterodimeric disintegrin from Echis carinatus, inhibits human and murine α4 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 echistatin (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 human cell lilies expressing alpha 4 beta 1 and alpha 4 beta 7 to immobilized VCAM-1; it has a lower inhibitory effect on alpha 5 beta 1-mediated cell adhesion. 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 same extent, EC3 inhibited adhesion of Jurkat cells and murine splenic lymphocytes 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 effect, We propose that the effect of EC3 is mediated, at least, in part, by blocking alpha 4 beta 1 and alpha 4 beta 7 on murine lymphocytes. (C) 2000 Academic Press.