Xk. Li et al., Fulminant hepatitis by Fas-ligand expression in MRL-lpr/lpr mice grafted with Fas-positive livers and wild-type mice with Fas-mutant livers, TRANSPLANT, 71(4), 2001, pp. 503-508
Background. Fulminant hepatitis in mice could be induced by gene-transfecti
on of Fas ligand (FasL). However, the mechanisms of this event still remain
controversial as to whether it is mediated by direct Fas/FasL interaction
and/or neutrophil migration. To investigate the role of exogenous FasL-expr
ession, we established a simple but clear mouse model on which we performed
liver transplantation between Fas-mutant mice (MRL-lpr/lpr) and wild-type
mice (MRL+/+).
Methods. The controls were nontransplanted wildtype (group 1) and MRL-lpr/l
pr (group 2) mice. We obtained recipients with a Fas defect only in the liv
er (group 3; MRL-lpr/lpr liver graft in wild-type mice) and Fas-defected re
cipients with Fas-positive livers (group 4; wild-type graft in MRL-lpr/lpr)
. We successfully expressed FasL in the liver by cotransfection of two type
s of adenoviral vectors, AxCALNFasL and AxCANCre, with a Cre-loxP switching
system.
Results. FasL-expression in the livers in groups 3 and 4 resulted in animal
death due to fulminant hepatitis within 48 hr after administration of the
vectors. We obtained similar findings in group 1, whereas the mice in group
2 survived without any evidence of hepatitis. Immune staining revealed a m
arked infiltration of CD11b-positive cells in group 1 and group 3, Despite
the number of apoptotic cells, a few infiltration of CD11b-positive cells w
ere seen in group 4. We observed no remarkable findings in the FasL-express
ed livers in group 2,
Conclusion. The results indicated that exogenous FasL-expression induces he
patocyte apoptosis both by direct interaction with Fas and by recruiting Fa
s-positive inflammatory cells. These findings are important for generating
a new strategy to prevent hepatitis as well as for understanding the role o
f the Fas/FasL interaction in the pathophysiology of hepatitis.