Treatment of toxic shock syndrome with endotoxin-neutralizing antibody

Abstract

The enhancement of host susceptibility to endotoxin (lipopolysaccharide, LPS) by toxic shock syndrome toxin-1 (TSST-1) is an important mechanism in the pathogenesis of toxic shock syndrome. In these studies, we sought to determine whether an endotoxin-neutralizing monoclonal antibody could be useful in the treatment of toxic shock syndrome. We isolated a murine monoclonal hybridoma (3-H3) which secreted monoclonal antibody (mAb) specific for Escherichia coli 0111:B4 LPS. Spleen cells cocultured with E. coli 0111:B4 LPS demonstrated up to a 60% decrease in mitogenic activity in the presence of 3-H3 mAb, but not control mAb, demonstrating that this antibody neutralized endotoxin in vitro. Rabbits pretreated with 3-H3 mAb or control mAb were injected intradermally with E. coli 0111:B4 LPS. One day later rabbits received E. coli 0111:B4 LPS intravenously to elicit the dermal Shwartzman reaction. Rabbits pretreated with 3-H3 mAb did not develop this reaction (0/6) compared to animals pretreated with control mAb (5/6), demonstrating that this antibody neutralized endotoxin in vivo ( P < 0.05). When this antibody was evaluated in a rabbit model of lethal toxic shock syndrome, rabbits pretreated with antibody demonstrated greater survival (8/14) than saline control animals (1/10) after challenge with TSST-1 and E. coli 0111:B4 LPS ( P < 0.05). Since the suspicion exists that low levels of endogenous LPS may potentiate TSST-1 activity during clinical toxic shock syndrome, we hypothesized that endotoxin-neutralizing antibodies could be useful in the treatment of this lethal disease process.