This study shows that overexpression of active TGF-beta1 in the knee joint results in OA-like changes and suggests the synovial lining cells contribute to the chondro-osteophyte formation.
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...
SUMMARYWe studied the effects of local IL-10 application, introduced by a recombinant human type 5 adenovirus vector, in the mouse knee joint during the early phase of CIA. One intra-articular injection with the IL-10-expressing virus (Ad5E1mIL-10) caused substantial over-expression of IL-10 in the mouse knee joint, using virus dosages which did not induce distracting inflammation. High expression of IL-10 was noted for a few days, being maximal at day 1. One intra-articular injection of Ad5E1mIL-10 in the knee joints of collagen type II (CII)-immunized mice, before onset of CIA was noted, reduced the incidence of collagen arthritis in that knee. Of high interest, the protective effect of local IL-10 expression by Ad5E1mIL-10 was not restricted to the knee joint alone. The arthritis incidence in the ipsilateral paw was highly suppressed. In contrast, local IL-10 over-expression was not effective when treatment was started after onset of CIA. Further analysis in the acute streptococcal cell wall-induced arthritis model revealed that local IL-10 over-expression markedly suppressed the production of tumour necrosis factoralpha (TNF-a ) and IL-1a , but had no significant effect on IL-1b and IL-12 production in the inflamed synovium. These data indicate that local over-expression of IL-10 in the knee joint of mice regulates the expression of collagen arthritis, probably through down-regulation of TNF-a .
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