Anticytotoxin-neutralizing antibodies in immune globulin preparations: potential use in hemolytic-uremic syndrome

The pathogenesis of primary (classic) hemolytic-uremic syndrome (HUS) is thought to be related to cytotoxin-producing enteric pathogens such as Shigella dysenteriae serotype 1 and Escherichia coli serotypes O157:H7 and 026:H11. The relevant cytotoxins include Shiga toxin and the closely related Shiga-like toxins (SLTs) produced by some E. coli strains. Intravenously administered immune globulin (IVIG) therapy has been reported to be beneficial in a few children with HUS. We therefore examined commercially available immune globulin preparations for the presence of anticytotoxin-neutralizing antibodies. Cytotoxicity and neutralization of the HUS-associated cytotoxins were quantitatively determined by means of a (3H)thymidine-labeled HeLa cell assay. The immune globulin preparations tested almost completely neutralized Shiga toxin (produced by S. dysenteriae 1) and SLT-I (produced by E. coli serotype 026:H11). Twofold dilutions of the preparations showed significant (p less than 0.01) neutralizing titers of 1:64 to 1:128. No significant neutralization (greater than 20%) of SLT-II (produced by E. coli strain C600 (933W] was noted. The IVIG preparation lost its inhibitory activity when passed through a protein A-Sepharose column, which bound immune globulin, indicating that its neutralizing effect is related to the antibody content. We also examined sera from 30 children without diarrhea or HUS; only one child had neutralizing titers against Shiga toxin (1:64) and SLT-I (1:128). Immune globulin preparations contain anticytotoxin-neutralizing antibodies, a finding that warrants further investigation of the therapeutic role of these preparations in early treatment of children with HUS related to Shiga toxin and SLT-I.