Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced th2activity.
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.
Boyle
D L
DL
Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, La Jolla, CA 92093-0656, USA.
Nguyen
K H
KH
Zhuang
S
S
Shi
Y
Y
McCormack
J E
JE
Chada
S
S
Firestein
G S
GS
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000628:therapy*; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007270:Injections, Intra-Articular; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology; D013643:Tarsus, Animal / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma