We have recently reported that local administration of anti-Fas monocl
onal antibody (MAb) in human T cell leukemia virus type 1 (HTLV-1) car
rying mice improved arthritis due to the induction of apoptosis. This
finding strongly indicated the beneficial therapeutic effect of Fas-me
diated apoptosis in rheumatoid arthritis (RA). To establish further th
e therapeutic effect of Fas-mediated apoptosis on RA taking into consi
deration safety and practicality, we investigated the effect of cells
transfected with human Fas ligand (hFasL) gene on proliferating human
rheumatoid synovium engrafted in severe combined immunodeficiency (SCI
D-RA) mice. The hFasL transfectants exhibited cytotoxic activity again
st RA synoviocytes via the Fas/FasL system in vitro. Histopathological
and immunohistochemical studies showed that local injection of irradi
ated-hFasL transfectants eliminated synoviocytes and mononuclear cell
in engrafted human rheumatoid synovium of SCID-RA mice. Furthermore, i
n situ nick end labeling analysis confirmed that the cell in engrafted
synovium frequently underwent apoptosis by irradiated-hFasL transfect
ants. Our results clearly demonstrated that hFasL transfectants induce
d apoptosis by cell-to-cell interaction via the Fas/FasL system. Thus,
ex vivo gene transfer of FasL may represent a novel therapeutic strat
egy for RA.