Endotoxin-induced uveitis is partially inhibited by anti-IL-8 antibody treatment.
OBJECTIVE
To examine the potential therapeutic effect of a neutralizing anti-IL-8 monoclonal antibody in endotoxin-induced uveitis (EIU) in the rabbit.


METHODS
An anti-IL-8 antibody (WS-4) was injected intravitreal 2 hours before, simultaneously with, or 6 hours after endotoxin challenge in rabbits. Eyes were examined for clinical signs of inflammation, and aqueous humor (AH) was sampled to study cellular infiltration and protein content. Leukocyte subset analysis was performed on Giemsa-stained AH cytospins. Histologic grading of inflammation was performed on hematoxylin-eosin-stained sagittal sections of enucleated eyes. In separate experiments, animals received the anti-IL-8 antibody simultaneously with the endotoxin challenge, before repeated anterior chamber paracentesis was performed (at 6, 12, 24, 48, and 72 hours after injection) to estimate the kinetics and durability of changes in total cell count and protein concentration in AH.


RESULTS
Anti-IL-8 therapy caused a decrease in the clinical and histologic grade of inflammation in EIU. The mean cell count in the AH at the peak of inflammation (24 hours) in eyes receiving endotoxin only was 6419+/-1165/microl (mean +/- SE) compared to 2546+/-573/microl in rabbits treated simultaneously with 250 microg of anti-IL-8 antibody (P < 0.05). The protein concentration in the AH was not significantly altered by anti-IL-8 treatment. Kinetic analysis of the leukocyte count in the AH demonstrated persistent inhibition of leukocyte accumulation (range, 60%-91% compared to control eyes) by the anti-IL-8 antibody administered simultaneously with endotoxin. This inhibition was sustained for up to 72 hours after injection.


CONCLUSIONS
Anti-IL-8 antibody treatment partially blocks EIU in rabbits. A consistent decrease in the recruitment of polymorphonuclear leukocytes into the anterior chamber was obtained when neutralizing antibody was injected simultaneously with endotoxin. These findings suggest that IL-8 contributes to the chemotactic signal for the recruitment of leukocytes in EIU.
Verma
M J
MJ
Inflammation Research Unit, School of Pathology, University of New South Wales, Sutherland Centre of Immunology, Sydney, Australia.
Mukaida
N
N
Vollmer-Conna
U
U
Matsushima
K
K
Lloyd
A
A
Wakefield
D
D
D000818:Animals; D000869:Anterior Eye Segment / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001082:Aqueous Humor / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D016209:Interleukin-8 / Q000276:immunology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides; D009504:Neutrophils / Q000276:immunology; D011817:Rabbits; D011994:Recombinant Proteins / Q000276:immunology; D012486:Salmonella typhimurium; D014606:Uveitis, Anterior / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology
D000911:Antibodies, Monoclonal; D005136:Eye Proteins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011994:Recombinant Proteins