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 chroni c inflammatory diseases such as rheumatoid arthritis. To determine the effi cacy of intra-articular IL-4 gene therapy in an animal model of arthritis u sing a retroviral vector a retrovirus encoding rat IL-4 (DA-IL-4) was engin eered, purified and concentrated to high titer (greater than or equal to 10 9 CFU/ml. Infectivity and expression levels were demonstrated in vitro usin g cultured fibroblast-like synoviocytes. Efficacy was evaluated in the rat adjuvant arthritis model. DA-IL-4 or DA-beta-gal retrovirus was injected in to the intra-articular joint space of the right ankle on day 12 after immun ization, Three days after joint injection, the injected paw contained incre ased levels of IL-4 compared with control or with the contralateral uninjec ted paw, demonstrating successful transgene expression. Surprisingly, 8 day s after treatment IL-4 levels continued to increase in the injected and con tralateral 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 tha t the transgene was expressed in the injected ankle hut not in the contrala teral joint. IL-4 gene therapy resulted in a significant reduction in paw s welling and decreased radiographic evidence of bone destruction. This is th e first demonstration of successful intra-articular retroviral gene treatme nt using a therapeutic gene. In addition to its antiinflammatory effect, th is study supports the potential application of infra-articular gene therapy as a method for enhancing systemic Th2 function.