Novel gene therapy for rheumatoid arthritis by FADD gene transfer: induction of apoptosis of rheumatoid synoviocytes but not chondrocytes

Synovial cells in the rheumatoid synovium show abnormal proliferation, lead ing to joint destruction. Rheumatoid synovial cells express functional Fas antigen and are susceptible to Fas-mediated apoptosis. We have proposed the induction of apoptosis by Fas/Fas ligand system of proliferative rheumatoi d synovium as a novel therapy for rheumatoid arthritis (RA). We have recent ly reported that Fas-associated death domain protein (FADD) plays a key rol e in Fas-mediated apoptosis of synovial cells in patients with RA. In this study, we determined whether FADD gene transfer could induce apoptosis of R A synoviocytes in vitro and in vivo. Transfection of FADD gene by adenovira l vector into cultured RA synoviocytes induced up-regulation of FADD expres sion and apoptosis. In addition, local injection of FADD adenovirus (Ad-FAD D) eliminated synoviocytes in vivo by induction of apoptosis of proliferati ng human rheumatoid synovium engrafted in severe combined immunodeficiency mouse, which is the most suitable animal model of RA for the evaluation of treatment strategy in vivo. In addition, Ad-FADD-induced apoptosis was limi ted to cells of the synovium tissue and did not affect chondrocytes. Our re sults strongly suggest that FADD gene transfer can induce apoptosis of RA s ynoviocytes both in vitro and in vivo, suggesting that FADD gene transfer m ight be effective in the treatment of RA.