Intra-articular electrotransfer of mouse soluble tumour necrosis factor receptor in a murine model of rheumatoid arthritis
Résumé
Background Rheumatoid arthritis (RA) is a chronic autoimmune diseasethat causes inflammation and destruction of the joints. In the collagen-induced arthritis mouse model of RA, we developed a nonviral gene therapymethod designed to block in situ the main cytokine tumour necrosis factor(TNF)-αMethods Electrotransfer was used to deliver a plasmid encoding extracellu-lar domain of mouse soluble TNF-α receptor type I fused to the Fc fragment ofmouse immunoglobulin (Ig)G1 (pTNFR-Is) corresponding to a dimeric TNF-αsoluble receptor fusion protein (mTNFR-Is/Ig).Results Delivery of the plasmid into the knees at symptom onset improvedthe histological inflammation and destruction not only at the knees, but alsoat the ankles, indicating a local and a regional therapeutic effect. The p lasmidwas detected in synovial membrane and meniscus specimens from the injectedjoints. In the synovial membrane, 15 days post-injection, interleukin (IL)-17and TNF-α mRNAs expression were increased, whereas IL-10 mRNA wasunchanged. However, the empty plasmid exerted a pro-inflammatory effect30 days post-injection.Conclusions These data indicate that local nonviral gene therapy againstTNF-α is effective, although further work is needed to decrease plasmidinduced inflammation.
