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Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

Gene Therapy volume 10, pages 1004–1011 (2003)Cite this article

Abstract

Elevated concentrations of interleukin-18 (IL-18) are found in both serum and synovial fluid of patients suffering from rheumatoid arthritis (RA) and this cytokine has recently been implicated in the development of experimental arthritis. In this present study, we developed an IL-18 neutralizing intervention and examined its efficacy for local intra-articular treatment of experimental arthritis. To this end we constructed an adenoviral vector containing the murine IL-18 binding protein isoform c gene (AdCMVIL-18BPc). The constructed adenoviral vector was validated on replication deficiency, transfection efficacy and ability to express biological functional IL-18BPc. Intra-articular overexpression of IL-18BPc significantly reduced incidence of collagen-induced arthritis (CIA) in treated kneejoints. Affected kneejoints of IL-18BPc-treated mice showed less severe arthritis, characterized by reduction of inflammation and destruction of bone and cartilage. Local intra-articular IL-1BPc treatment in both knees provided additional protection against CIA incidence and severity in distal paws. Measurement of serum levels of specific collagen type (CII) Abs revealed a moderate reduction of circulating IgG2a anti-CII Abs, while IgG1 anti-CII Abs remained at similar level. The present study underlines the involvement of IL-18 as an important proinflammatory cytokine in onset of experimental arthritis. Furthermore, it shows that endogenous IL-18 can be blocked efficiently through local adenoviral overexpression of IL-18BPc, indicating that treatment with IL-18BPc might contribute to joint protection in RA.

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Acknowledgements

We thank Inneke Verschueren (Department of Internal Medicine, University Medical Center Nijmegen) for determination of TNFα levels in provided samples.

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Author notes

  1. F A J van de Loo: This study was supported by the Dutch Arthritis Association (Grant No. 99-2-403)

Authors and Affiliations

  1. Rheumatology Research Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands

    R L Smeets, F A J van de Loo, O J Arntz, M B Bennink, L A B Joosten & W B van den Berg

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  1. R L Smeets
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  2. F A J van de Loo
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  3. O J Arntz
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  4. M B Bennink
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Smeets, R., van de Loo, F., Arntz, O. et al. Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice. Gene Ther 10, 1004–1011 (2003). https://doi.org/10.1038/sj.gt.3301986

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