Local interferon-β gene therapy ameliorates adjuvant arthritis in rats

Objective

Interferon (IFN)-β is thought to inhibit the expression of proinflammatory cytokines and to enhance the production of anti-inflammatory proteins such as IL-1Ra. More recently it was shown that IFN-β is important in maintaining homeostasis of bone resorption. Because systemic treatment does not appear to be effective in RA patients possibly because of the short half-life of IFN protein, we studied the potential of intra-articular gene therapy using an adenoviral vector to determine whether local constitutive expression of IFN-β in the joint might have a beneficial effect.

Methods

Three different dosages (109, 1010 and 1011 viral particles) of an adenoviral vector containing the gene for rat IFN-β or LacZ (Ad.IFN-beta and Ad.LacZ) were injected into the right ankle joints of rats with adjuvant arthritis (AA) on day 12 after adjuvant immunization. Joints were harvested 2 weeks later. The effect of IFN-β on paw swelling measured by plethysmometry, bone degradation and histologic joint damage was assessed.

Results

In the rats treated with the highest dose of Ad.IFN-beta reduced paw swelling was observed (P = 0.022 Ad.IFN-beta versus Ad.LacZ). In addition, a clear reduction in paw swelling was seen in the left uninjected paw. Moreover, the IFN-β-treated animals had significantly less cartilage and bone destruction (P = 0.05) in both the right and left paws as compared with control animals.

Conclusion

We demonstrate that adenoviral in vivo gene transfer of IFN-β cDNA into the synovium reduces the severity of inflammation of AA in rats. In addition, an even more potent effect was found on articular cartilage and bone destruction. Furthermore, injection of Ad.IFN-beta into a single paw can suppress inflammation and joint degradation in the contralateral joints. Thus, treatment of a single joint by local delivery of the IFN-β gene could protect multiple joints.