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, leading 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 rheumatoid synovium as a novel therapy for rheumatoid arthritis (RA). We have recently reported that Fas-associated death domain protein (FADD) plays a key role in Fas-mediated apoptosis of synovial cells in patients with RA. In this study, we determined whether FADD gene transfer could induce apoptosis of RA synoviocytes in vitro and in vivo. Transfection of FADD gene by adenoviral vector into cultured RA synoviocytes induced up-regulation of FADD expression and apoptosis. In addition, local injection of FADD adenovirus (Ad-FADD) eliminated synoviocytes in vivo by induction of apoptosis of proliferating 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 limited to cells of the synovium tissue and did not affect chondrocytes. Our results strongly suggest that FADD gene transfer can induce apoptosis of RA synoviocytes both in vitro and in vivo, suggesting that FADD gene transfer might be effective in the treatment of RA.