Prevention of murine collagen‐induced arthritis in the knee and ipsilateral paw by local expression of human interleukin‐1 receptor antagonist protein in the knee

Abstract

Objective. To determine the efficacy of local human interleukin-1 receptor antagonist (HuIL-1Ra) gene therapy in murine collagen-induced arthritis (CIA).Methods. DBN1 mice were immunized against bovine type I1 collagen. Before the onset of arthritis, NIH/3T3 fibroblasts transfected with pMFG-IRAP were transplanted into the knee cavity. Normal NIH/3T3 cells served as controls. Paws were evaluated macroscopically for redness, swelling, and deformities during the course of arthritis. Swelling of the knee joints was measured by external gamma counting of 99"technetium accumulation in the joint. Paws and knee joints were dissected and processed for histologic studies to evaluate inflammation and cartilage destruction.Results. The NIH/3T3 fibroblasts survived in the joint cavity of DBA mice for at least 7 days. The transduced cells expressed immunoreactive and bioactive HuIL-1Ra in the knee joint, and produced sufficient amounts to block the effect of 1 ng of recombinant murine IL-la on chondrocyte proteoglycan synthesis. The onset of CIA was almost completely prevented in knee joints containing HuIL-1Ra-producing cells, whereas joints containing normal cells showed severe inflammation and destruction of cartilage. Moreover, onset of CIA in the draining joints (ipsilateral paws) of the HuIL-1Ra gene-bearing knees was also prevented.Conclusion. Local production of HuIL-1Ra in the knee was able to ameliorate the effects of IL-1 on cartilage and could prevent the onset of CIA not only in Address reprint requests to Andrew C. Bakker, Department of Rheumatology, PO Box 9101,6500 HB Nijmegen, The Netherlands.Submitted for publication September 20, 1996; accepted in revised form December 6, 1996. that knee, but also in the "draining" paw. This indicates the feasibility of gene transfer as a therapeutic approach to modulating arthritis.Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive joint destruction and immobility. Prevention of cartilage erosion and dysfunction would be of great therapeutic benefit to patients. There is convincing evidence that the cytokines tumor necrosis factor a (TNFa) and interleukin-1 (IL-1) play a decisive role in arthritic processes. This is based on neutralizing studies in various models of experimental arthritis (1-8) and recent observations from clinical trials in patients with R A (9-12). Prolonged treatment with antibodies, scavenging receptors, or receptor antagonists is probably needed to obtain sustained control, and in that respect, a gene therapy approach might offer a valuable alternative.Gene therapy in experimental arthritis has been proposed by Bandara et a1 (13), and their first study in rabbits showed that local injection of synovial cells that had been transduced in vitro with human interleukin-1 receptor antagonist (HuIL-1Ra) complementary DNA could inhibit the effects of IL-1 injection into the knee joint (14,15). Recently, the efficacy of such an approach was also demonstrated in antigen-induced arthritis in the rabbit and bacterial cell wall-ind...

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

“…Similar observations have been made after intra-articular treatment of CIA with IL-1 receptor antagonist, which also results in amelioration of the CIA in the distal paws of treated mice. 25,26 Whether these effects are the result of a direct local inhibition of cytokine spillover and antigen release by reduced inflammation or caused by leakage of IL18BPc to distal joints remains to be established. When comparing incidence versus severity in the distal paws of IL-18BP-treated animals, IL-18 significantly reduced incidence while increase in severity of affected hind paws could not be halted.…”

“…24 Therefore, in some situations it appears preferable to choose local instead of systemic treatment. Studies by Bakker et al 25,26 already showed functionality of local intra-articular therapy for arthritis using IL-1 receptor antagonist.…”

Anakinra, a recombinant human interleukin‐1 receptor antagonist (r‐metHuIL‐1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo‐controlled trial

“…Administration of IL-1Ra, either systemically or locally by gene transfer, reduces inflammation and joint damage in animal models of RA (20)(21)(22)(23). A recombinant form of human IL-1Ra, anakinra (recombinant methionyl human IL-1 receptor antagonist [r-metHuIL-1ra]), is a competitive antagonist of IL-1 that blocks the actions of IL-1 without any detectable agonist activity.…”

An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

“…The 'contralateral effect', that is the administration of the expression vector in one joint to suppress arthritis in distal or contralateral joints, has been reported by many laboratories. [47][48][49][50][51][52] This study, which shows activation of the IL-1/IL-6 enhancer-promoter in the contralateral joints by signals derived from the arthritic joint, suggests that there is crosstalk between joints. Treatment of one joint may interfere with this crosstalk and by this suppresses arthritis in the other contralateral joint.…”