Natural killer cell may impair liver regeneration in fulminant hepatic failure.
The authors established a new experimental model of fulminant hepatic failure (FHF) with prolonged hepatocellular necrosis and impaired liver regeneration, and evaluated the immunological mechanisms related to the impaired liver regeneration in this model. A novel lipid A analogue, FS-112, was injected intravenously into male Balb/c mice, followed by a 70% partial hepatectomy 2 days later. Serum levels of T.Bil. and ALT rose 7 days after the partial hepatectomy, as compared with controls. In mice pretreated with FS-112, labeling indices of both BrdU and PCNA 36 hrs after the partial hepatectomy were significantly lower than those in the controls. Splenic lymphocytes harvested from the FHF mice 1-5 days after the partial hepatectomy showed a cytotoxic activity against regenerating hepatocytes with a peak effect on day 5. Cytotoxic activity against YAC-1 cells was also found up to 5 days after the partial hepatectomy, and resembled that directed against the regenerating hepatocytes. On the 5th day of FS-112 administration, there was a marked rise in the production of IFN-gamma from splenocytes. When FK-506, an immunosuppressive agent, was given intracutaneously daily for 7 days, serum levels of T.Bil. and ALT significantly decreased, as compared with controls. Furthermore, the PCNA-labeling index 36 hrs after the partial hepatectomy was enhanced by the administration with FK-506 in the FHF mice. These results strongly suggest that the NK cells activated by IFN-gamma may be involved in killing the regenerating liver cells, and thus play a role in the pathogenesis of the impaired liver regeneration in FHF.2+ recovery from the impaired liver regeneration in FHF.
Ohnishi
H
H
First Department of Internal Medicine, Gifu University School of Medicine, Japan.
Muto
Y
Y
Maeda
T
T
Hayashi
T
T
Nagaki
M
M
Yamada
T
T
Shimazaki
M
M
Yamada
Y
Y
Sugihara
J
J
Moriwaki
H
H
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006501:Hepatic Encephalopathy / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D013154:Spleen / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use
D007371:Interferon-gamma; D016559:Tacrolimus