Anti-CD14 mAb treatment provides therapeutic benefit after in vivo exposure to endotoxin.
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.
Schimke
J
J
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Mathison
J
J
Morgiewicz
J
J
Ulevitch
R J
RJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004731:Endotoxins / Q000633:toxicity; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D011817:Rabbits
D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors