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inflammation-inducible intra-articular production of human IL-1 receptor antagonist results in a more efficient inhibition of collagen-induced arthritis than does constitutive expression of the same transgene

Objective

To achieve disease-inducible expression of recombinant anti-inflammatory proteins in order to allow autoregulation of drug dose by natural homeostatic mechanisms.

Method

We compared a disease-inducible, two component expression system (C3-Tat/HIV) with the constitutive cytomegalovirus (i.e. CMV) promoter in the polyarticular collagen-induced arthritis (CIA) model. DBA/I mice were immunized with bovine type II collagen and boostered on day 22. On day 22, mice without any clinical signs of arthritis were selected and 10e7 PFU of the adenoviral vectors (Ad5.CMV-Luc, Ad5.CMV-IL-1Ra, or Ad5.C3-Tat/HIV-IL-1Ra) that contained either luciferase (Luc) or the human IL-1Ra gene under control of one of the two promoters were used to transfect the synovial lining of both knees. The injected knee joints and ipsilateral paws were then scored for signs of arthritis and at the end histology was taken.

Results

Inducible promoter-driven IL-1Ra expression resulted in significantly improved inhibition of CIA than did CMV-driven IL-1Ra production. Moreover, overexpression of IL-1Ra in the knee joints also prevented CIA in the ipsilateral paws.

Conclusion

Our data demonstrate the feasibility of an inducible expression system for producing a transgene for treatment of arthritis; and show that this system is more effective than strong, constitutive transgene expression for preventing collagen-induced arthritis in mice.

Acknowledgement

This study was financially supported by the Dutch Arthritis Association (941) and the Dutch Organization for Scientific Research (902-27-218).

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Keywords

  • Knee Joint
  • Efficient Inhibition
  • Synovial Lining
  • Component Expression
  • Bovine Type