Therapeutic administration of anti-PcrV F(ab')(2) in sepsis associated with Pseudomonas aeruginosa.
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.
Shime
N
N
Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA.
Sawa
T
T
Fujimoto
J
J
Faure
K
K
Allmond
L R
LR
Karaca
T
T
Swanson
B L
BL
Spack
E G
EG
Wiener-Kronish
J P
JP
D000818:Animals; D000907:Antibodies, Bacterial / Q000378:metabolism / Q000627:therapeutic use*; D000942:Antigens, Bacterial / Q000276:immunology*; D016470:Bacteremia / Q000382:microbiology / Q000503:physiopathology / Q000628:therapy; D001427:Bacterial Toxins / Q000276:immunology*; D006439:Hemodynamics; D007116:Immunization, Passive; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000378:metabolism / Q000627:therapeutic use; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D052899:Pore Forming Cytotoxic Proteins; D011552:Pseudomonas Infections / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000302:isolation & purification / Q000472:pathogenicity; D011817:Rabbits; D018805:Sepsis / Q000382:microbiology / Q000503:physiopathology / Q000628:therapy*; D012772:Shock, Septic / Q000382:microbiology / Q000503:physiopathology / Q000628:therapy; D015996:Survival Rate
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D052899:Pore Forming Cytotoxic Proteins; C118546:antigen V, Pseudomonas