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IC14, an anti-CD14 antibody, inhibits endotoxin-mediated symptoms and inflammatory responses in humans
A Verbon1, P E Dekkers, T ten Hove
1Department of Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. A.Verbon@amc.uva.nl
Abstract:
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.
Insights
Blocking CD14 with IC14 antibody reduced lipopolysaccharide (LPS)-induced inflammation in healthy humans. This study demonstrates CD14 blockade as a potential therapeutic strategy for sepsis by reducing inflammatory responses.
Area of Science:
- Immunology
- Microbiology
- Pharmacology
Background:
- CD14 acts as a receptor for bacterial cell wall components, initiating inflammatory responses relevant to sepsis.
- Lipopolysaccharide (LPS) is a key trigger for sepsis-related inflammation.
- Understanding CD14's role in LPS response is crucial for developing anti-sepsis therapies.
Purpose of the Study:
- To investigate the role of CD14 in LPS-induced effects in humans.
- To evaluate the efficacy of IC14, a monoclonal antibody against CD14, in mitigating LPS responses.
- To provide in vivo proof of principle for CD14 blockade in reducing LPS responsiveness.
Main Methods:
- 16 healthy subjects received intravenous LPS injection (4 ng/kg).
- Subjects were pre-treated with either intravenous IC14 (1 mg/kg) or placebo 2 hours prior to LPS.
- CD14 saturation on monocytes and granulocytes, clinical symptoms, cytokine release, leukocyte and endothelial cell activation, and phagocytosis were assessed.
Main Results:
- IC14 achieved >90% CD14 saturation on circulating immune cells at LPS injection.
- IC14 significantly attenuated LPS-induced clinical symptoms and proinflammatory cytokine release.
- IC14 partially inhibited leukocyte and endothelial cell activation and the acute phase response, with minimal impact on phagocytosis.
Conclusions:
- IC14 blockade effectively reduces LPS-induced inflammatory responses in humans.
- These findings establish CD14 blockade as a viable therapeutic strategy for sepsis.
- Targeting CD14 offers a promising approach to manage sepsis by dampening excessive inflammation.
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