Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis.
Publication year
2001Source
Journal of Clinical Investigation, 108, 12, (2001), pp. 1825-1832ISSN
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Publication type
Article / Letter to editor

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Organization
Rheumatology
Internal Medicine
Journal title
Journal of Clinical Investigation
Volume
vol. 108
Issue
iss. 12
Page start
p. 1825
Page end
p. 1832
Subject
Chronic arthritis: Pathogenesis and treatment; Chronische arthritis: Pathogenese en behandelingAbstract
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.
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- Faculty of Medical Sciences [81055]
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