Protective effects of anti-C5a peptide antibodies in experimental sepsis.
We evaluated antibodies to different peptide regions of rat C5a in the sepsis model of cecal ligation and puncture (CLP) for their protective effects in rats. Rabbit polyclonal antibodies were developed to the following peptide regions of rat C5a: amino-terminal region (A), residues 1-16; middle region (M), residues 17-36; and the carboxyl-terminal region (C), residues 58-77. With rat neutrophils, the chemotactic activity of rat C5a was significantly inhibited by antibodies with the following rank order: anti-C > anti-M >> anti-A. In vivo, antibodies to the M and C (but not A) regions of C5a were protective in experimental sepsis, as determined by survival over a 10-day period, in a dose-dependent manner. The relative protective efficacies of anti-C5a preparations (in descending order of efficacy) were anti-C > anti-M >> anti-A. In CLP rats, a delay in infusion of antibodies, which were injected at 6 or 12 h after CLP, still resulted in significant improvement in survival rates. These in vivo and in vitro data suggest that there are optimal targets on C5a for blockade during sepsis and that delayed infusion of anti-C5a antibody until after onset of clinical evidence of sepsis still provides protective effects.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
M S
MS
Huber-Lang
J V
JV
Sarma
S R
SR
McGuire
K T
KT
Lu
R F
RF
Guo
V A
VA
Padgaonkar
E M
EM
Younkin
I J
IJ
Laudes
N C
NC
Riedemann
J G
JG
Younger
P A
PA
Ward
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D015936:Complement C5a / Q000276:immunology*; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects*; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D012756:Sheep; D015996:Survival Rate
D000906:Antibodies; D010455:Peptides; D015936:Complement C5a