Author(s):
|
Plater-Zyberk, C.;
Joosten, L.A.B.
;
Helsen, M.M.A.
; Sattonnet-Roche, P.; Siegfried, C.; Alouani, S.;
Loo, F.A.J. van de
; Graber, P.; Aloni, S.; Cirillo, R.;
Lubberts, G.J.H.
;
Dinarello, C.A.
;
Berg, W.B. van den
; Chvatchko, Y.
|
Subject:
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Chronic arthritis: Pathogenesis and treatment Chronische arthritis: Pathogenese en behandeling |
Organization:
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Rheumatology Internal Medicine |
Journal title:
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Journal of Clinical Investigation
|
Abstract:
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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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