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Anti-CD14 mAb treatment provides therapeutic benefit after in vivo exposure to endotoxin
J Schimke1, J Mathison, J Morgiewicz
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
The presence of endotoxin from Gram-negative bacteria signals the innate immune system to up-regulate bacterial clearance and/or killing mechanisms. Paradoxically, such responses also contribute to septic shock, a clinical problem occurring with high frequency in Gram-negative septicemia. CD14 is a receptor for endotoxin (lipopolysaccharide, LPS) and is thought to have an essential role in innate immune responses to infection and thereby in the development of septic shock. Using a novel rabbit model of endotoxic shock produced by multiple exposures to endotoxin, we show that anti-rabbit CD14 mAb, which blocks LPS-CD14 binding, protects against organ injury and death even when the antibody is administered after initial exposures to LPS. In contrast, anti-rabbit tumor necrosis factor mAb treatment fails to protect when administered after LPS injections. These results support the concept that anti-CD14 treatment provides a new therapeutic window for the prevention of pathophysiologic changes that result from cumulative exposures to LPS during septic shock in man.
Insights
Blocking CD14, a receptor for endotoxin (lipopolysaccharide, LPS), protects against organ injury and death in a rabbit model of septic shock. This suggests anti-CD14 therapy may offer a new treatment window for endotoxin-induced shock.
Area of Science:
- Immunology
- Pathophysiology
Background:
- Gram-negative bacteria endotoxin (lipopolysaccharide, LPS) triggers innate immune responses.
- These responses paradoxically contribute to septic shock, a life-threatening condition.
- CD14 is a key receptor for LPS, mediating innate immune responses and septic shock development.
Purpose of the Study:
- To investigate the therapeutic potential of blocking LPS-CD14 interaction in a novel rabbit model of endotoxic shock.
Main Methods:
- A novel rabbit model of endotoxic shock was established using multiple LPS exposures.
- Anti-rabbit CD14 monoclonal antibody (mAb) was administered to block LPS-CD14 binding.
- Anti-rabbit tumor necrosis factor (TNF) mAb was used as a comparative treatment.
Main Results:
- Anti-CD14 mAb administration, even after initial LPS exposure, protected rabbits from organ injury and death.
- In contrast, anti-TNF mAb treatment failed to protect when given after LPS injections.
- These findings highlight the critical role of CD14 in mediating endotoxic shock progression.
Conclusions:
- Blocking the LPS-CD14 interaction with anti-CD14 mAb offers a promising therapeutic strategy.
- This approach may provide a new therapeutic window for preventing pathophysiological changes in human septic shock.
- Targeting CD14 presents a novel therapeutic avenue for managing Gram-negative bacterial infections and associated septic shock.