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We have recently demonstrated Fas-mediated apoptosis in the synovium of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA.

We have recently reported that local administration of antiactivity against RA synoviocytes via the Fas/FasL system Fas monoclonal antibody (MAb) in human T cell leukemia in vitro. Histopathological and immunohistochemical studvirus type 1 (HTLV-1) carrying mice improved arthritis due ies showed that local injection of irradiated-hFasL transfecto the induction of apoptosis. This finding strongly indicated tants eliminated synoviocytes and mononuclear cells in the beneficial therapeutic effect of Fas-mediated apoptosis engrafted human rheumatoid synovium of SCID-RA mice. in rheumatoid arthritis (RA). To establish further the theraFurthermore, in situ nick end labeling analysis confirmed peutic effect of Fas-mediated apoptosis on RA taking into that the cells in engrafted synovium frequently underwent consideration safety and practicality, we investigated the apoptosis by irradiated-hFasL transfectants. Our results effect of cells transfected with human Fas ligand (hFasL) clearly demonstrated that hFasL transfectants induced gene on proliferating human rheumatoid synovium apoptosis by cell-to-cell interaction via the Fas/FasL sysengrafted in severe combined immunodeficiency (SCIDtem. Thus, ex vivo gene transfer of FasL may represent a RA) mice. The hFasL transfectants exhibited cytotoxic novel therapeutic strategy for RA.

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Our results suggest that Fas-mediated apoptosis of RA synoviocytes is differentially regulated by TNFalpha and bFGF. In addition, the regulatory mechanisms of apoptosis involve the formation of the death-inducing signaling complex, especially at the level of caspase 8 activation, and this process may be partly associated with FLIP expression.

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Objective. Fas-mediated apoptosis is observed in synoviocytes of patients with rheumatoid arthritis (RA), but not in those of patients with osteoarthritis (OA). The present study was conducted to elucidate the mechanisms that initiate induction of Fas-mediated apopto-sis in RA synoviocytes. Methods. Cultured OA synoviocytes, which are insensitive to Fas-mediated apoptosis in spite of Fas antigen expression, were used in these experiments. Synovial cell proliferation and cytotoxicity studies were performed using MTS and lactate dehydrogenase release assays. Surface expression of Fas antigen was analyzed by flow cytometry. The expression and function of apoptosis-signaling molecules, such as caspase 8 and caspase 3, were examined by immunoblot analysis. Results. Tumor necrosis factor (TNF) induced proliferation of cultured OA synoviocytes. Fas ligation with anti-Fas monoclonal antibody (mAb) resulted in cytotoxic activity against cultured OA synoviocytes that had been pretreated with TNF for 5 days, but not those pretreated for 2 days. In contrast, anti-Fas mAb did not show a cytotoxic effect against untreated cultured OA synoviocytes. A gradual up-regulation of caspase 8 and caspase 3, which played a role in the caspase cascade for Fas-mediated apoptosis, was observed in TNF-treated

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