Fulminant hepatitis by Fas-ligand expression in MRL-lpr/lpr mice grafted with Fas-positive livers and wild-type mice with Fas-mutant livers

Citation
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
Citations number
23
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research Diagnosis & Treatment
Journal title
TRANSPLANTATION
ISSN journal
0041-1337 → ACNP
Volume
71
Issue
4
Year of publication
2001
Pages
503 - 508
Database
ISI
SICI code
0041-1337(20010227)71:4<503:FHBFEI>2.0.ZU;2-0
Abstract
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.