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Tlr4/md-2 monoclonal antibody therapy affords protection in experimental models of septic shock

Academic Article
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Overview

authors

  • Daubeuf, B.
  • Mathison, J.
  • Spiller, S.
  • Hugues, S.
  • Herren, S.
  • Ferlin, W.
  • Kosco-Vilbois, M.
  • Wagner, H.
  • Kirschning, C. J.
  • Ulevitch, Richard
  • Elson, G.

publication date

  • November 2007

journal

  • Journal of Immunology  Journal

abstract

  • 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.

subject areas

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antibodies, Monoclonal
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Disease Models, Animal
  • Humans
  • Immunotherapy
  • Ligands
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Mice
  • Shock, Septic
  • Survival Rate
  • Toll-Like Receptor 4
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 17947685
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Additional Document Info

start page

  • 6107

end page

  • 6114

volume

  • 179

issue

  • 9

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