Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced th2activity.

Abstract

Gene therapy has been explored as a potential method for 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 (>/=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 rats. RT-PCR studies demonstrated that the transgene was expressed in the injected ankle but 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 anti-inflammatory effect, this study supports the potential application of intra-articular gene therapy as a method for enhancing systemic Th2 function.

• Authors: D L Boyle, K H Nguyen, S Zhuang, Y Shi, J E McCormack, S Chada, G S Firestein
• Journal: Gene therapy (Gene Ther) Vol. 6 Issue 12 Pg. 1911-8 (Dec 1999) ISSN: 0969-7128 [Print] England
• PMID: 10637442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Arthritis, Experimental (immunology, therapy)
• Cells, Cultured
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage)
• Humans
• Injections, Intra-Articular
• Interferon-gamma (analysis)
• Interleukin-4 (administration & dosage, metabolism, therapeutic use)
• Male
• RNA, Messenger (analysis)
• Rats
• Rats, Inbred Lew
• Retroviridae (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Synovial Membrane (immunology)
• Tarsus, Animal (immunology)
• Th2 Cells (immunology)