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The Journal of Immunology, 2001, 167: 5880-5886.
Copyright © 2001 by The American Association of Immunologists

Therapeutic Administration of Anti-PcrV F(ab')2 in Sepsis Associated with Pseudomonas aeruginosa1

Nobuaki Shime*,§, Teiji Sawa*, Junichi Fujimoto*, Karine Faure*, Leonard R. Allmond*, Timur Karaca*, Britta L. Swanson*, Edward G. Spack and Jeanine P. Wiener-Kronish2,*,{dagger},{ddagger}

* Department of Anesthesia and Perioperative Care, {dagger} Department of Medicine, and {ddagger} 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-{alpha} 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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