Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced Th2 activity

Gene therapy has been explored as a potential method for I: treating chronic inflammatory diseases such as rheumatoid arthritis. To determine the efficacy of intra-articular IL-4 gene therapy in an animal model of arthritis using a retroviral vector a retrovirus encoding rat IL-4 (DA-IL-4) was engineered, purified and concentrated to high titer (greater than or equal to 109 CFU/ml. Infectivity and expression levels were demonstrated in vitro using cultured fibroblast-like synoviocytes. Efficacy was evaluated in the rat adjuvant arthritis model. DA-IL-4 or DA-beta-gal retrovirus was injected into the intra-articular joint space of the right ankle on day 12 after immunization, Three days after joint injection, the injected paw contained increased levels of IL-4 compared with control or with the contralateral uninjected paw, demonstrating successful transgene expression. Surprisingly, 8 days after treatment IL-4 levels continued to increase in the injected and contralateral paw compared with DA-beta-gal-treated animals. Serum IL-4 levels were also elevated in DA-IL-4-treated mts. RT-PCR studies demonstrated that the transgene was expressed in the injected ankle hut not in the contralateral joint. IL-4 gene therapy resulted in a significant reduction in paw swelling and decreased radiographic evidence of bone destruction. This is the first demonstration of successful intra-articular retroviral gene treatment using a therapeutic gene. In addition to its antiinflammatory effect, this study supports the potential application of infra-articular gene therapy as a method for enhancing systemic Th2 function.