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Biotech / Medical : Indications -- Sepsis/Acute Inflammation
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From: tnsaf2/9/2009 1:35:07 PM
   of 89
 
Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4
Published online before print January 30, 2009
doi: 10.1073/pnas.0808146106

Abstract

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from Gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of Gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in Gram-negative sepsis, we first showed that TLR4-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice were fully resistant to Escherichia coli–induced septic shock, whereas TLR2-/- and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1–334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for Gram-negative sepsis.

© 2009 by The National Academy of Sciences of the USA
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