ANTIBODIES AGAINST CD14 PROTECT PRIMATES FROM ENDOTOXIN-INDUCED SHOCK

Lipopolysaccharide (LPS), residing in the outer membrane of all gram-n egative bacteria, is considered a major initiating factor of the gram- negative septic shock syndrome in humans. LPS forms a complex with the LPS binding protein (LBP) in plasma, and LPS-LBP complexes engage a s pecific receptor, CD14, on the surface of myeloid cells, leading to th e production of potent proinflammatory cytokines. The major goal of th is study was to test the importance of the CD14 pathway in vivo in a p rimate model that is similar to human septic shock. Primates were pret reated with one of two different inhibitory anti-CD14 mAbs, then chall enged with intravenous endotoxin (375 mu g/kg/h) for 8 h. The anti-CD1 4 treatment regimens were successful in preventing profound hypotensio n, reducing plasma cytokine levels (TNF-alpha, IL-1 beta, IL-6, and IL -8), and inhibiting the alteration in lung epithelial permeability tha t occurred in animals treated with LPS and an isotype-matched control antibody. These results demonstrate for the first time the importance of the CD14 pathway in a primate model that is similar to human septic shock. Inhibition of the CD14 pathway represents a novel therapeutic approach to treating this life-threatening condition.