Adenoviral mediated delivery of FAS ligand to arthritic joints causes extensive apoptosis in the synovial lining

Background Rheumatoid arthritis (RA) is an autoimmune disease where the syn ovial lining layer of the joint becomes thickened, hypercellular, and highl y aggressive. Invading synovial tissue erodes cartilage and subchondral bon e and leads to loss of joint function. FasL, a cell-surface molecule on act ivated T-cells interacts with its receptor, Fas, to induce apoptosis in tar get cells. We addressed the Feasibility of using adenoviral gene transfer o f FasL therapeutically to mediate apoptosis in arthritic joints similar in size to the small joints of the hands and feet that are the primary sites o f RA in humans. Methods Adenoviral vectors were used to transfer FasL and LacZ cDNAs into h uman RA and rabbit synovial fibroblasts in culture where apoptosis was eval uated using MTT and TUNEL analyses. The ability of Ad.FasL to mediate synov ial apoptosis in vivo was then addressed in an IL-1-induced arthritis model in the rabbit knee. Results In culture, delivery of FasL was found to efficiently induce apopto sis in both human RA and rabbit synovial fibroblasts. The ability of Ad.Fas L to induce synovial apoptosis was then evaluated in rabbit knee joints. 24 h after intra-articular injection of 10(11) Ad.FasL particles, large regio ns of synovial tissue were observed histologically consisting primarily of fibrous matrix and cellular debris. TUNEL staining of corresponding section s was highly positive for fragmented DNA. Glycosaminoglycan (GAG) synthesis from cartilage shavings from treated joints suggests that Ad.FasL does not induce significant apoptosis in resident articular chondrocytes. Conclusions Infection of human and rabbit synovial fibroblasts with Ad.FasL results in significant apoptotic cell death in vitro. Direct intraarticula r injection of Ad.FasL in the arthritic rabbit knee results in extensive ap optosis in the synovium without affecting chondrocyte viability. Copyright (C) 2000 John Wiley & Sons, Ltd.