Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis.
Two distinct IL-18 neutralizing strategies, i.e. a rabbit polyclonal anti-mouse IL-18 IgG and a recombinant human IL-18 binding protein (rhIL-18BP), were used to treat collagen-induced-arthritic DBA/1 mice after clinical onset of disease. The therapeutic efficacy of neutralizing endogenous IL-18 was assessed using different pathological parameters of disease progression. The clinical severity in mice undergoing collagen-induced arthritis was significantly reduced after treatment with both IL-18 neutralizing agents compared to placebo treated mice. Attenuation of the disease was associated with reduced cartilage erosion evident on histology. The decreased cartilage degradation was further documented by a significant reduction in the levels of circulating cartilage oligomeric matrix protein (an indicator of cartilage turnover). Both strategies efficiently slowed disease progression, but only anti-IL-18 IgG treatment significantly decreased an established synovitis. Serum levels of IL-6 were significantly reduced with both neutralizing strategies. In vitro, neutralizing IL-18 resulted in a significant inhibition of TNF-alpha, IL-6, and IFN-gamma secretion by macrophages. These results demonstrate that neutralizing endogenous IL-18 is therapeutically efficacious in the murine model of collagen-induced arthritis. IL-18 neutralizing antibody or rhIL-18BP could therefore represent new disease-modifying anti-rheumatic drugs that warrant testing in clinical trials in patients with rheumatoid arthritis.
Plater-Zyberk
C
C
Serono Pharmaceutical Research Institute, Geneva, Switzerland. Rheumatology Research Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Joosten
L A
LA
Helsen
M M
MM
Sattonnet-Roche
P
P
Siegfried
C
C
Alouani
S
S
van De Loo
F A
FA
Graber
P
P
Aloni
S
S
Cirillo
R
R
Lubberts
E
E
Dinarello
C A
CA
van Den Berg
W B
WB
Chvatchko
Y
Y
D000818:Animals; D001168:Arthritis / Q000097:blood / Q000628:therapy*; D003094:Collagen / Q000276:immunology*; D006023:Glycoproteins / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D006023:Glycoproteins; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D015850:Interleukin-6; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C118370:interleukin-18 binding protein; D007371:Interferon-gamma; D003094:Collagen