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,
*
Department of Anesthesia and Perioperative Care,
Department of Medicine, and
Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
Department of Anesthesiology and Intensive Care, Kyoto Prefectural University of Medicine, Kyoto, Japan; and
¶ InterMune, Inc., Brisbane, CA 94005
The effects of rabbit-derived polyclonal Ab against PcrV, a protein
involved in the translocation of type III secreted toxins of
Pseudomonas aeruginosa, was investigated in two animal
models of P. aeruginosa sepsis. In a mouse survival
study, the i.v. administration of anti-PcrV IgG after the airspace
instillation of a lethal dose of P. aeruginosa resulted
in the complete survival of the animals. In a rabbit model of septic
shock associated with Pseudomonas-induced lung injury,
animals treated with anti-PcrV IgG intratracheally or i.v. had
significant decreases in lung injury, bacteremia, and plasma TNF-
and significant improvement in the hemodynamic parameters associated
with shock compared with animals treated in a similar manner with
nonspecific control IgG. The administration of anti-PcrV
F(ab')2 showed protective effects comparable to those of
whole anti-PcrV IgG. These results document that the therapeutic
administration of anti-PcrV IgG blocks the type III secretion
system-mediated virulence of P. aeruginosa and prevents
septic shock and death, and that these protective effects are largely
Fc independent. We conclude that Ab therapy neutralizing the type III
secretion system has significant potential against lethal P.
aeruginosa infections.
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