SUPPRESSION OF EXPERIMENTAL ARTHRITIS BY GENE-TRANSFER OF INTERLEUKIN-1 RECEPTOR ANTAGONIST CDNA

Restoration of the impaired balance between pro- and antiinflammatory cytokines should provide effective treatment of rheumatoid arthritis. Gene therapy has been proposed as an approach for delivery of therapeu tic proteins to arthritic joints, Here, we examined the efficacy of an tiinflammatory gene therapy in bacterial cell wall-induced arthritis i n rats, Human secreted interleukin 1 receptor antagonist (sIL-1ra) was expressed in joints of rats with recurrent bacterial cell wall-induce d arthritis by using ex vivo gene transfer. To achieve this, primary s ynoviocytes were transduced in culture with a retroviral vector carryi ng the sIL-1ra cDNA, Transduced cells were engrafted in ankle joints o f animals prior to reactivation of arthritis, Animals in control group s were engrafted with synoviocytes transduced with lacZ and neo marker genes, Cells continued to express transferred genes for at least 9 da ys after engraftment. We found that gene transfer of sIL-1ra significa ntly suppressed the severity of recurrence of arthritis, as assessed b y measuring joint swelling and by the gross-observation score, and att enuated but did not abolish erosion of cartilage and bone. The effect of intraarticularly expressed sIL-1ra was essentially local, as there was no significant difference in severity of recurrence between unengr afted contralateral joints in control and experimental groups. We esti mate that locally expressed sIL-1ra was about four orders of magnitude more therapeutically efficient than systemically administered recombi nant sIL-1ra protein. These findings provide experimental evidence for the feasibility of antiinflammatory gene therapy for arthritis.