Weili Gu

Diverse Effects of FK506 on the Apoptosis of Hepatocytes and Infiltrating Lymphocytes in an Allografted Rat Liver

BACKGROUND The current study investigated whether FK506 (FK) regulates the apoptotic systems in allografted rat liver and the contribution of Fas/Fas-ligand system and Bcl-2 family during acute rejection. MATERIALS AND METHODS The recipients were divided into three groups, the allo, the allo-FK, and the syn group. Rats were euthanized 1, 3, 5, and 7 d after OLT. Apoptotic activity was explored using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. The expression of Fas/Fas-ligand and Bcl-2/Bax in the grafted livers was investigated by Western blotting and immunohistochemistry. RESULTS The apoptotic index (AI) of hepatocytes in the allo-FK group was less than that in the allo group. Fas in the allo group was more intense than that in the allo-FK group in the periportal areas on day 1 and 3, while Bcl-2 in the allo group was less intense than that in the allo-FK group in the pericaval areas at all time-points after OLT. CONCLUSION FK provides beneficial antiapoptotic effects on hepatocytes in the grafted rat livers through both the down-regulation of Fas expression in the periportal areas and the up-regulation of Bcl-2 expression in the pericaval areas.

CD4 T-Cell Regulation of Cytotoxic T Cells During the Induction Phase of Liver-Induced Spontaneous Tolerance in Rats

PurposeTo check for in vivo CD4 T-cell-mediated inhibition of the immune response in rats with spontaneously accepted liver transplants.MethodsUsing the Lewis to Wistar Furth rat strain combination, we performed transient in vivo depletion of CD4 T-cells by anti-CD4 monoclonal antibodies (mAb) after liver transplantation. We used the CTL assay to detect primed T cells. We also retransplanted a grafted donor liver, parked for 3 days, into a secondary naive recipient rat.ResultsWhen Lewis rat livers were transplanted into the recipient Wistar Furth rats, the grafts suffered an early immune attack, followed by spontaneous acceptance without immunosuppression. However, giving anti-CD4 mAb to the recipients at the time of grafting prolonged the acute rejection reaction. Furthermore, giving anti-CD4 therapy on postoperative days (PODs) 21 and 35, but not on PODs 56 and 100, induced transient liver damage in recipients overcoming acute rejection. No primed T cells were detected by the CTL assay in the recipient rats within 2 months after transplantation. Meanwhile, the retransplanted liver had no ability to elicit an immune attack.ConclusionsCD4 T cells seemed to downregulate the effector function of T cells, but not T-cell proliferation in this model.

Rapid loss of graft immunogenicity and transient hyporesponsiveness to the donor antigen after rat liver transplantation

Title Rapid Loss of Graft Immunogenicity and Transient Hyporesponsiveness to The Donor Antigen After Rat Liver Transplantation Author(s) Gu, Weili; Yamaguchi, Junzo; Hashimoto, Toshiaki; Yamamoto, Takao; Nakayama, Eiichi; Kanematsu, Takashi Citation Acta medica Nagasakiensia. 1999, 44(3-4), p.31-38 Issue Date 1999-12-15 URL http://hdl.handle.net/10069/16143 Right NAOSITE: Nagasaki Universitys Academic Output SITE

Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the PH and sham groups 14 days after operation. However, compared with those in the sham group, the livers in mice in the PH+BDL group had a smaller size, a lower cell proliferative activity, and more fibrotic tissue 14 days after the operation, suggesting the insufficient regeneration of the cholestatic liver. Pathway-focused array analysis showed that many genes were up- or down-regulated over 1.5-fold in both PH+BDL and PH groups at 1, 3, 7, and 14 days after treatment. Interestingly, more genes that were functionally related to the extracellular matrix and inflammatory chemokines were found in the PH+BDL group than in the PH group at 7 and 14 days after treatment. Our data suggest that up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

Cytotoxic T‐cell elimination during anti‐CD4–induced rat liver acceptance and rapid replacement of functional graft antigen–presenting cells

In previous studies, we showed that primed T cells were eliminated in long‐term survival Wistar Furth (WF) recipient rats with spontaneously accepted Lewis (LEW) liver graft and that the grafted liver lost the ability to elicit rejection reaction early after liver transplantation. We hypothesized that the same phenomenon may be observed in tolerant animals after immunosuppression in a rejector rat strain combination (WF→LEW). Furthermore, we proposed the repopulation of liver allograft with host antigen–presenting cells rapidly after transplantation. Recipient LEW rats that underwent anti‐CD4 therapy accepted the WF liver allografts after a transient rejection reaction. In tolerant animals, alloreactive CD8 T cell precursors were present, but primed T cells were absent. Intraperitoneal challenge with grafted WF liver homogenates obtained from recipient LEW rats on day 4 after transplantation did not induce transient rejection responses in long‐term survival recipient LEW rats, a finding that differed from the results of experiments using normal WF liver homogenates. However, challenge with grafted WF liver homogenates, similar to those of normal LEW liver homogenates, induced rejection responses in long‐term survival recipient WF rats with LEW liver allograft. Flow cytometric analysis confirmed that most of nonparenchymal cells in the grafted WF liver were recipient (LEW) genotype. These observations showed that the deletional mechanism of effector T cells also is observed in this setting, and professional donor antigen–presenting cells are replaced by those of recipient genotype within the graft during the early phase of transplantation. (Liver Transpl 2004;10:734–742.)

Alanyl‐glutamine provides beneficial nutritional support after orthotopic transplantation of the liver in pigs

We evaluated the nutritional status of pigs that received glutamine after orthotopic liver transplantation. After transplantation, one group of pigs received an oral diet (group I,n=5), one group received conventional total parenteral nutrition (group II,n=4), and one group received alanylglutamine supplemented parenteral nutrition (group III,n=7). We compared nutritional status, graft liver function, and ileal mucosal thickness in the three groups. There were no significant differences in nutritional parameters or serum chemistries among the groups. In terms of ileal integrity, mucosal thickness was reduced after liver transplantation in group II, whereas it was relatively well preserved in group III. The level of endotoxin in the portal venous blood was significantly lower in group III, than in group II on the 7th day after liver transplantation. Parenteral alanyl-glutamine appears to have beneficial effects in preserving the integrity of the ileal mucosa when oral intake of nutrients may not be feasible. This could prevent bacterial translocation in the portal vein.