TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock

J Immunol. 2007 Nov 1;179(9):6107-14. doi: 10.4049/jimmunol.179.9.6107.


Overactivation of the immune system upon acute bacterial infection leads to septic shock. Specific bacterial products potently stimulate immune cells via toll-like receptors (TLRs). Gram-negative bacteria induce a predominantly TLR4-driven signal through LPS release. To neutralize LPS signaling in experimental models of sepsis, we generated mAbs toward the TLR4/myeloid differentiation protein-2 (MD-2) complex. The binding properties of an array of selected rat mAbs differed in respect to their specificity for TLR4/MD-2 complex. The specificity of one such mAb, 5E3, to murine TLR4 was confirmed by its recognition of an epitope within the second quarter of the ectodomain. 5E3 inhibited LPS-dependent cell activation in vitro and prevented proinflammatory cytokine production in vivo following LPS challenge in a dose-dependent manner. Furthermore, 5E3 protected mice from lethal shock-like syndrome when applied using both preventative and therapeutic protocols. Most notably, in the colon ascendens stent peritonitis model of polymicrobial abdominal sepsis, administration of a single dose of 5E3 (50 mug) protected mice against mortality. These results demonstrate that neutralizing TLR4/MD-2 is highly efficacious in protecting against bacterial infection-induced toxemia and offers TLR4/MD-2 mAb treatment as a potential therapy for numerous clinical indications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / therapeutic use*
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Disease Models, Animal
  • Humans
  • Immunotherapy
  • Ligands
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Antigen 96
  • Mice
  • Shock, Septic / chemically induced
  • Shock, Septic / immunology*
  • Shock, Septic / metabolism
  • Shock, Septic / therapy*
  • Survival Rate
  • Toll-Like Receptor 4 / immunology*
  • Toll-Like Receptor 4 / metabolism


  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal
  • Ligands
  • Lipopolysaccharides
  • Ly96 protein, mouse
  • Lymphocyte Antigen 96
  • Toll-Like Receptor 4