Inhibition of Production of Tumor Necrosis Factor by Monoclonal Antibodies to Lipopolysaccharides

Abstract

Murine monoclonal antibodies to lipopolysaccharides (LPS) from rough J5 mutant of Escherichia coli O111:B4 protected D-galactosamine-treated mice against lethal effects of LPS and provided protection in an experimental infection model with live E. coli. Three previously prepared anti-LPS antibodies were evaluated for ability to inhibit LPS-induced tumor necrosis factor (TNF) secretion. In vivo, TNF production was induced in mice treated with D-galactosamine and challenged with LPS. Two antibodies (D6B3 and D6B4) decreased serum TNF levels and prevented lethal effects of LPS. Nonprotective anti-LPS antibody (D9A2) and an unrelated antibody to neomycin did not reduce circulating TNF levels after LPS challenge. Pretreatment of mice with D6B3 and D6B4 protected mice from infection with E. coli and prevented serum TNF increases induced by E. coli infection. In nonprotected animals, high levels of TNF were detected in serum 3-6 h after infection; animals died within 24 h. In vitro, addition of protective antibodies to macrophage cultures at initiation of LPS stimulation inhibited TNF production. Nonprotective antibody D9A2 failed to block LPS-induced TNF production.