ANTI-CD14 MAB TREATMENT PROVIDES THERAPEUTIC BENEFIT AFTER IN-VIVO EXPOSURE TO ENDOTOXIN

The presence of endotoxin from Gramnegative bacteria signals the innat e immune system to upregulate bacterial clearance and/or killing mecha nisms. Paradoxically, such responses also contribute to septic shock, a clinical problem occurring with high frequency in Gramnegative septi cemia. CD14 is a receptor for endotoxin (lipopolysaccharide, LPS) and is thought to have an essential role in innate immune responses to inf ection and thereby in the development of septic shock. Using a novel r abbit model of endotoxic shock produced by multiple exposures to endot oxin, we show that anti-rabbit CD14 mAb, which blocks LPS-CD14 binding , protects against organ injury and death even when the antibody is ad ministered after initial exposures to LPS, In contrast, anti-rabbit tu mor necrosis factor mAb treatment fails to protect when administered a fter LPS injections. These results support the concept that anti-CD14 treatment provides a new therapeutic window for the prevention of path ophysiologic changes that result from cumulative exposures to LPS duri ng septic shock in man.