Potential withdrawal of rheumatoid synovium by the induction of apoptosis using a novel in vivo model of rheumatoid arthritis

Abstract

Objective. To investigate whether Fas-mediated apoptosis has potential as a new therapeutic strategy in rheumatoid arthritis (RA) by use of a novel model of' RA in which human RA tissue is grafted into SCID mice. Methods. Fresh rheumatoid synovial tissue including joint cartilage was grafted subcutaneously into the backs of SCID mice. Six weeks after engraftment, anti-Fas monoclonal antibody was injected intraperito-neally. Time-related apoptotic changes caused by anti-Fas monoclonal antibody in grafted synovium were evaluated by nick end-labeling histochemistry. Results. Thirty-six hours after the injection, diffuse apoptotic changes were observed in the grafted synovia. Four weeks after the injection, rheumatoid synovial tissue diminished. ConcZusion. This is the first report concerning the present effectiveness of anti-Fas monoclonal antibody in diminishing rheumatoid synovium in vivo, and suggests the possibility of a new strategy for treating rheumatoid arthritis by inducing Fas-mediated apoptosis. Rheumatoid arthritis (RA) is a chronic inflam-matory disorder characterked by hyperplasia of the

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

“…This mouse is considered a suitable model of RA, because engrafted human rheumatoid synovium into SCID mice maintains the histologic components of rheumatoid synovia. 10,17 In this system, we showed the disappearance of synoviocytes in engrafted synovia injected with Ad-FADD but not Ad-LacZ. Moreover, TUNEL-positive cells were observed only in tissues injected with Ad-FADD.…”

“…10,17 The distribution of locally injected adenoviral vector was examined by the expression of ␤- Injection of Ad-FADD induces apoptosis of rheumatoid synovium engrafted in SCID-RA mice Finally, to confirm that the cell death induced by infection with Ad-FADD in the above studies was due to apoptosis, we examined the presence of DNA fragmentation in engrafted rheumatoid synovium by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method. As shown in Figure 6, TUNEL-positive cells were frequently observed in engrafted rheumatoid synovium injected with Ad-FADD ( Figure 6b).…”

“…10,17 After joint surgery, the human tissue specimen was quickly engrafted into female SCID mice aged 6 to 7 weeks. All mice were handled under specific pathogen-free conditions.…”

The Fas - Fas Ligand apoptotic pathway

“…Indeed, these cells are sensitive in vitro to anti-Fas monoclonal antibody-induced apoptosis Sakai et al, 1998) particularly in RA synovium . The Fas receptor has also been detected on human chondrocytes (Kim et al, 1999) and osteoblasts (Nakashima et al, 1998).…”

Protective effects of HFE7A, mouse anti-human/mouse Fas monoclonal antibody against acute and lethal hepatic injury induced by Jo2

“…There have been some reported attempts of the application of anti-Fas antibodies to therapeutic agents against diseases resulting from defects in Fas-mediated apoptosis (Nishimura-Morita et al 1997;Fujisawa et al 1996;Nakajima et al 1995;Firestein et al 1995;Sakai et al 1998). The administration of anti-mouse Fas monoclonal antibody (mAb) RK-8 to FasL-deficient MRLgld/gld mice reduced the autoimmune symptoms, including those of lymphadenopathy, nephrotisis, arthritis and vasculitis (Nishimura-Morita et al 1997).…”