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Open Access Research article

A comparative study of the inhibitory effects of interleukin-1 receptor antagonist following administration as a recombinant protein or by gene transfer

Jean-Noel Gouze123, Elvire Gouze12, Glyn D Palmer12, Victor S Liew12, Arnulf Pascher12, Oliver B Betz12, Thomas S Thornhill2, Christopher H Evans12, Alan J Grodzinsky3 and Steven C Ghivizzani12*

Author Affiliations

1 Center for Molecular Orthopaedics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

2 Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

3 Center for Biomedical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

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Arthritis Res Ther 2003, 5:R301-R309  doi:10.1186/ar795

Published: 1 August 2003

Abstract

Anakinra, the recombinant form of IL-1 receptor antagonist (IL-1Ra), has been approved for clinical use in the treatment of rheumatoid arthritis as the drug Kineret™, but it must be administered daily by subcutaneous injection. Gene transfer may offer a more effective means of delivery. In this study, using prostaglandin E2 production as a measure of stimulation, we quantitatively compared the ability of anakinra, as well as that of IL-1Ra delivered by gene transfer, to inhibit the biologic actions of IL-1β. Human synovial fibroblast cultures were incubated with a range of doses of anakinra or HIG-82 cells genetically modified to constitutively express IL-1Ra. The cultures were then challenged with recombinant human IL-1β either simultaneously with addition of the source of IL-1Ra or 24 hours later. In a similar manner, the potencies of the two sources of IL-1Ra were compared when human synovial fibroblasts were challenged with IL-1β produced constitutively by genetically modified cells. No significant difference in inhibitory activity was observed between recombinant protein and IL-1Ra provided by the genetically modified cells, under static culture conditions, even following incubation for 4 days. However, under culture conditions that provided progressive dilution of the culture media, striking differences between these methods of protein delivery became readily apparent. Constitutive synthesis of IL-1Ra by the genetically modified cells provided sustained or increased protection from IL-1 stimulation over time, whereas the recombinant protein became progressively less effective. This was particularly evident under conditions of continuous IL-1β synthesis.

Keywords:
arthritis; gene therapy; IL-1; IL-1 receptor antagonist; synoviocytes