2000 Fiscal Year Final Research Report Summary
Pathogenesis of immune-mediated cholangiopathy
| Project/Area Number |
11670473
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | Tohoku University |
|---|
Principal Investigator |
UENO Yoshiyuki Tohoku University Hospital, Research Associate, 医学部・附属病院, 助手 (70282126)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MANO Yutaka Tohoku University Hospital, Research Associate, 医学部・附属病院, 助手 (50302120)
|
|---|
| Project Period (FY) |
1999 – 2000
|
| Keywords | Bile Duct Epithelial Cells / Apoptosis / Fas (CD95) / Fas ligand (FasL) / GVHD |
|---|
| Research Abstract |
Bile duct injury observed in hepatic graft versus host disease (GVHD) is regarded as an immune-mediated injury, although its precise mechanism is unclear. However, recent studies have suggested the involvement of Fas-mediated cell death in this immune-mediated cholangiopathy. In this study, we first demonstrated the constitutive expression of Fas receptor by cholangiocytes in situ from normal BALB/c mice, which was upregulated in GVHD mice. Also, we confirmed the Fas protein expression in the isolated cholangiocytes from normal BALB/c mice by immunocytochemistry and immunoblotting. Furthermore, the addition of agonistic Fas antibody (Jo2) induced cholangiocyte apoptosis confirmed by DNA-ladder formation and annexin V staining. Cholangiocytes from Fas-deficient mice (MRL lpr/lpr) did not show Jo2-induced apoptosis. Interferon γ augmented Fas expression and Fas-mediated cell death, respectively. Following these observations, experimental GVHD was induced by transfer of splenocytes from B10.D2 mice to irradiated (800 rad) BALB/c mice. Liver infiltrating lymphocytes from the recipient showed dose-dependent cytotoxicity against ^<51>Cr-labeled cholangiocytes isolated from BALB/c mice. Moreover, the addition of blocking Fas-Fc fusion protein reduced this cytotoxicity to 44.7%. Finally, administration of this Fas-Fc protein to the BALB/c mice, which had been adoptively transferred with splenocytes of B10.D2 mice, prevented the development of hepatic GVHD in vivo. These results demonstrated the involvement of Fas-mediated cell death in cholangiopathy observed in GVHD, and a soluble Fas-Fc protein may have a therapeutic potential for hepatic GVHD.
|
Research Products
(8 results)
