IC14, an anti-CD14 antibody, inhibits endotoxin-mediated symptoms and inflammatory responses in humans.
CD14 is a receptor for cell wall components of Gram-negative and Gram-positive bacteria that has been implicated in the initiation of the inflammatory response to sepsis. To determine the role of CD14 in LPS-induced effects in humans, 16 healthy subjects received an i.v. injection of LPS (4 ng/kg) preceded (-2 h) by i.v. IC14, a recombinant chimeric mAb against human CD14, at a dose of 1 mg/kg over 1 h, or placebo. In subjects receiving IC14, saturation of CD14 on circulating monocytes and granulocytes was >90% at the time of LPS injection. IC14 attenuated LPS-induced clinical symptoms and strongly inhibited LPS-induced proinflammatory cytokine release, while only delaying the release of the anti-inflammatory cytokines soluble TNF receptor type I and IL-1 receptor antagonist. IC14 also inhibited leukocyte activation, but more modestly reduced endothelial cell activation and the acute phase protein response. The capacity of circulating monocytes and granulocytes to phagocytose Escherichia coli was only marginally reduced after infusion of IC14. These data provide the first proof of principle that blockade of CD14 is associated with reduced LPS responsiveness in humans in vivo.
Verbon
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A
Department of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. A.Verbon@amc.uva.nl
Dekkers
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ten Hove
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Hack
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Pribble
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JP
Turner
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Souza
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Axtelle
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Hoek
F J
FJ
van Deventer
S J
SJ
van der Poll
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D000209:Acute-Phase Proteins / Q000378:metabolism; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D016466:CHO Cells; D006224:Cricetinae; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019446:Endotoxemia / Q000097:blood / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007958:Leukocyte Count; D018950:Lipopolysaccharide Receptors / Q000097:blood / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics
D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins