Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome

The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children. The role of a verocytotoxin (VT)-producing Escherichi a coli has been strongly implicated in the epidemic form of HUS, Although d irect toxicity of VT on glomerular endothelial cells has been demonstrated, it remained still un clear how the VT is transported from the intestine to the target organs. In this study we demonstrate that VT, when incubated in whole blood, binds rapidly end completely to human polymorphonuclear leuko cytes (PMNs) and not to other components of blood, Binding studies with I-1 25-VT-1 showed a single class of binding sites on freshly isolated, nonstim ulated human PMNs, The K-d Of VT-binding to PMNs was 10(-8) mol/L, 100-fold less than that of the VT-receptor globotriaosylceramide. On incubation of VT-preloaded PMNs with human glomerular microvascular endothelial cells (GM VECs), transfer of VT-1 to the endothelial cells occurred. Incubation of no nstimulated GMVECs with VT-preloaded PMNs, but not with PMNs or VT-1 alone, caused inhibition of protein synthesis and cell death, Our date are in con cert with a role of PMNs in the transfer of VT from the intestine to the ki dney endothelium, This transfer occurs by selective binding to a specific r eceptor on PMNs and subsequent passing of the ligand VT to the VT-receptor on GMVECs, which causes cell damage, This new mechanism further underpins t he important role of PMNs in HUS, (Blood, 2000;95:3396-3402) (C) 2000 by Th e American Society of Hematology.