Antibodies against CD14 protect primates from endotoxin-induced shock.

Leturcq, Didier; Moriarty, Ann; Talbott, G. Douglas; Winn, Robert K.; Martin, Thomas R.; Ulevitch, Richard J.

doi:10.1172/jci118945

Cited by 144 publications

(94 citation statements)

References 32 publications

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“…Our results may appear inconsistent with earlier studies that demonstrated that animals lacking CD14 or treated with a CD14-specific mAb are protected against endotoxin-mediated shock (12,15). These divergent results are probably due to the fact that those earlier studies employed purified LPS or bacteria that were administered systemically, whereas we used live bacteria that were deposited on a mucosal surface.…”

Section: Discussioncontrasting

confidence: 99%

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Blockade of CD14 Increases Shigella-Mediated Invasion and Tissue Destruction

Wennerås

Avé

Huerre

et al. 2000

The Journal of Immunology

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Shigella is a diarrheal pathogen that causes disease through invasion of the large intestinal mucosa. The endotoxin of the invading bacterium may play a key role in the disease process by causing inflammation and tissue injury during infection. Earlier studies have shown that various animal species lacking functional CD14 were protected against endotoxin-mediated shock. Rabbits experimentally infected with Shigella were used to test the hypothesis that blockade of endotoxin-induced cell activation with anti-CD14 mAb would diminish inflammation and thus disease severity. Unexpectedly, we observed that the intestinal mucosa of anti-CD14-treated animals exhibited a 50-fold increase in bacterial invasion and more severe tissue injury compared with controls. Despite higher bacterial loads in treated animals, the numbers of polymorphonuclear leukocytes that were recruited to the infection site were similar to those in controls. Furthermore, the phagocytic cells of CD14-blocked animals produced IL-1 and TNF-α. Moreover, in vitro blockade of CD14 did not impede bactericidal activity. Thus, anti-CD14 treatment interfered with host defense mechanisms involved with removal/eradication of Shigella.

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Section: Discussioncontrasting

confidence: 99%

“…Primates that were treated with monoclonal anti-CD14 Ab i.v. did not develop endotoxic shock after LPS infusion (15). Anti-CD14 treatment also protected rabbits from organ injury and death elicited by repeated administration of LPS i.v.…”

Section: Blockade Of Cd14 Increasesmentioning

confidence: 86%

Blockade of CD14 Increases Shigella-Mediated Invasion and Tissue Destruction

Wennerås

Avé

Huerre

et al. 2000

The Journal of Immunology

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“…Inhibition of the CD14 pathway represents an experimental method to prevent septic shock (Leturcq et al 1996) in primates and rabbits (Schimke et al 1998). The administration of CD14-antibodies was effective in preventing septic shock even when administered after LPS exposure.…”

Section: Membrane-associated Moleculesmentioning

confidence: 99%

Induction and characterization of endotoxin tolerance in equine peripheral blood mononuclear cells in vitro

Frellstedt

McKenzie

Barrett

et al. 2012

Veterinary Immunology and Immunopathology

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Endotoxemia is responsible for severe illness in horses. Individuals can become unresponsive to the endotoxin molecule after an initial exposure; this phenomenon has been called developing a state of 'endotoxin tolerance' (ET). ET has been induced in horses in vivo; however, cytokine expression associated with ET has not been investigated. The purpose of this study was to develop and validate a method for inducing ET in equine peripheral blood mononuclear cells (PBMCs) in vitro, and to describe the cytokine profile which is associated with the ET.Blood was collected from 6 healthy horses and PBMCs were isolated. ET was induced by culturing cells with three concentrations of endotoxin given to induce ET, and evaluated after a second dose of endotoxin given to challenge the cells. The relative mRNA expression of IL-10 and IL-12 was measured by use of quantitative PCR.ET was induced in all cells (n=6) exposed to the 2-step endotoxin challenge. In PBMCs treated with 1.0 ng/ml of endotoxin followed by challenge with 10 ng/ml of endotoxin, the relative mRNA expression of IL-10 in tolerized cells was not different from positive control cells. In contrast, the relative mRNA expression of IL-12 in tolerized cells was decreased by 15-fold after the second endotoxin challenge compared with positive control cells.This experiment demonstrated a reliable method for the ex vivo induction of ET in equine PBMCs. A marked suppression of IL-12 production is associated with ET. The production of IL-10 was not altered in ET in our model.

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“…The crucial role of CD14 in LPS signaling has been confirmed with knock-out mice; CD14-deficient mice are highly resistant to septic shock initiated by injection of either LPS or live bacteria (11). The CD14 pathway has been suggested as a therapeutic target because anti-CD14 monoclonal antibodies gave significant protection against septic shock in animal models (12,13). In addition to the LPS of Gram-negative bacteria, CD14 can bind other microbial products such as peptidoglycan (PGN), lipoteichoic acid, lipoarabinomannan, and lipoproteins (14,15).…”

mentioning

confidence: 99%

Crystal Structure of CD14 and Its Implications for Lipopolysaccharide Signaling

Kim

Lee

Jin

et al. 2005

Journal of Biological Chemistry

238

242

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Lipopolysaccharide, the endotoxin of Gram-negative bacteria, induces extensive immune responses that can lead to fatal septic shock syndrome. The core receptors recognizing lipopolysaccharide are CD14, TLR4, and MD-2. CD14 binds to lipopolysaccharide and presents it to the TLR4/MD-2 complex, which initiates intracellular signaling. In addition to lipopolysaccharide, CD14 is capable of recognizing a few other microbial and cellular products. Here, we present the first crystal structure of CD14 to 2.5 Å resolution. A large hydrophobic pocket was found on the NH 2 -terminal side of the horseshoelike structure. Previously identified regions involved in lipopolysaccharide binding map to the rim and bottom of the pocket indicating that the pocket is the main component of the lipopolysaccharide-binding site. Mutations that interfere with lipopolysaccharide signaling but not with lipopolysaccharide binding are also clustered in a separate area near the pocket. Ligand diversity of CD14 could be explained by the generous size of the pocket, the considerable flexibility of the rim of the pocket, and the multiplicity of grooves available for ligand binding.

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Antibodies against CD14 protect primates from endotoxin-induced shock.

Cited by 144 publications

References 32 publications

Blockade of CD14 Increases Shigella-Mediated Invasion and Tissue Destruction

Blockade of CD14 Increases Shigella-Mediated Invasion and Tissue Destruction

Induction and characterization of endotoxin tolerance in equine peripheral blood mononuclear cells in vitro

Crystal Structure of CD14 and Its Implications for Lipopolysaccharide Signaling

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