Rheumatoid arthritis is characterized by hyperplasia of synovial membrane and bone destruction. Fibroblast-like synoviocytes play an important role in the pathogenesis of rheumatoid arthritis because of their proliferation and secretion of an impressive array of cytokines/chemokines, adhesion molecules and proteases, which result in the progressive bone and joint destruction. Up regulation of apoptosis can be one way of regulating and preventing excess fibroblast-like cell proliferation and the growth of inflammatory synovium. Fas protein expression has been identified in the synovial cells from RA patients, but Fas ligand (FasL) needed for apoptosis seems to be lacking. Adenovirus mediated FasL intra-articular gene transfer suppresses the progression of autoimmune arthritis on animal model by inducing apoptosis in the synovium. Patterns of which cells were apoptotic were not shown. Our pilot data show fibroblast-like synoviocytes can be infected by adenovirus-mouse FasL as well as undergo apoptosis after infection in a dose dependent fashion and the inflammatory synovium from RA patient can be eliminated in situ in a RA-SCID mouse model by mouse Fas ligand gene transfer. In this proposal, we are constructing plasmid and producing recombinant adenovirus carrying human FasL gene and GFP maker (hFasL-GFP) in the same vector to identify whether FasL induced apoptosis in human synovial fibroblasts and synovium in vitro and in a RA-SCID mice model in vivo undergo the bystander effects. We will clarify the possible side effects involved in FasL gene transfer, such as the induction of pro-inflammatory cytokines/chemokines production in synovial fibroblasts and synovium, and the effects on the viability and metabolism of chondrocytes in vivo with a long term and multiple FasL gene transfer in order to find approaches to overcome them. The above investigation should elucidate mechanism, tools and toxicity related to FasL gene transfer intra-articularlly, and has a high likelihood of being, translated into a novel approach for treating arthritis patients at the inflammatory site in the clinic. Our long-range goals are the development of a novel therapeutic approach--"""""""" Gene Scalpels"""""""" for arresting inflammatory synovium. at an early stage of arthritis by intra-articular administration of an apoptosis inducer, such as FasL, using a suitable vector system, which may replace the treatment of synovectomy for some arthritis patients.
| Zhang, Haidi; Gao, Guangping; Clayburne, Gilda et al. (2005) Elimination of rheumatoid synovium in situ using a Fas ligand 'gene scalpel'. Arthritis Res Ther 7:R1235-43 |
