C3‐Tat/HIV–regulated intraarticular human interleukin‐1 receptor antagonist gene therapy results in efficient inhibition of collagen‐induced arthritis superior to cytomegalovirus‐regulated expression of the same transgene

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Abstract
Objective: To achieve disease‐inducible expression of recombinant antiinflammatory proteins in order to allow autoregulation of drug dose by natural homeostatic mechanisms.Methods: We compared the inducible 2‐component expression system (C3–human immunodeficiency virus/transactivator of transcription [C3‐Tat/HIV]) with the constitutive cytomegalovirus (CMV) promoter in the polyarticular collagen‐induced arthritis (CIA) model in mice. DBA/1 mice were immunized with bovine type II collagen and were given boosters on day 21. On day 22, mice were injected intraarticularly with the adenoviral vectors AdCMVLuc, AdCMVhIL‐1Ra, AdC3‐Tat/HIV‐Luc, or AdC3‐Tat/HIV‐hIL‐1Ra. The injected knee joints and hind paws were then scored for signs of arthritis, and knee joint histology was compared.Results: The CMV‐driven interleukin‐1 receptor antagonist (IL‐1Ra) expression resulted in a high constitutive expression and amelioration of CIA. C3‐Tat/HIV–driven IL‐1Ra expression could be detected only on days 24, 29, and 35. Fourteen days after injection of the vectors, CIA was significantly better inhibited by the C3‐Tat/HIV–driven IL‐1Ra expression compared with the CMV‐driven IL‐1Ra expression. Moreover, prevention of CIA in the knee joints also prevented CIA in the untreated hind paws.Conclusion: Our data demonstrate for the first time the feasibility of an inducible expression system for local production of IL‐1Ra for treatment of arthritis in the CIA model.

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