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Zhao J.,Research Center for Biological Therapy | Zhang Z.,Research Center for Biological Therapy | Luan Y.,CAS Institute of Biophysics | Zou Z.,Center for Non Infectious Liver Diseases | And 8 more authors.
Hepatology | Year: 2014

It is well established that interleukin (IL)-22 has hepatoprotective and antifibrotic functions in acute liver injury models; however, its function in patients with liver fibrosis and liver cirrhosis (LC) remains obscure. In the current study, we demonstrated that expression of numerous IL-22 pathway-associated genes was significantly up-regulated in hepatitis B virus (HBV)-infected liver tissues, compared to normal controls, through microarray analysis. In agreement with these findings, liver-infiltrating IL-22+ cells were largely increased in HBV-infected patients with LC, compared to those without LC or healthy subjects, and were positively associated with liver fibrosis staging scores. Immunohistochemistry and flow cytometric analyses revealed that IL-22 was produced by multiple intrahepatic immune cells and, preferentially, by T-helper (Th) 17 cells in LC patients. In an HBV transgenic (Tg) mouse model of T-cell-mediated chronic liver inflammation and fibrosis, blockade of IL-22 attenuated hepatic expression of chemokine (C-X-C motif) ligand 10 and chemokine (C-C motif) ligand 20 (CCL20) and subsequently reduced Th17 recruitment and liver inflammation and fibrosis progression. In vitro treatment with IL-22 stimulated hepatic stellate cells (HSCs) to secrete several chemokines and subsequently promoted Th17 cell chemotaxis. Blocking C-X-C chemokine receptor type 3 or CCL20 reduced Th17 cell chemotaxis by IL-22-treated HSCs. Conclusions: IL-22 plays a pathological role in exacerbating chronic liver inflammation and fibrosis by recruiting hepatic Th17 cells in HBV-infected patients and HBV Tg mice. © 2014 by the American Association for the Study of Liver Diseases.


Liu Z.,Research Center for Liver Transplantation | Yu X.,Peking University | Ren W.,Peking University | Zhang M.,Research Center for Liver Transplantation | And 5 more authors.
Transplantation Proceedings | Year: 2014

Purpose. To investigate CD152 and PD-1 expression on T lymphocytes and the function of CD152- and PD-1epositive CD8 T cells in human acute liver allograft rejection. Materials and methods. Sixty-three patients undergoing liver transplantation were enrolled in this study, including 26 cases with acute allograft rejection (Gr-AR) and 37 cases with stable allograft liver function (Gr-SF). The expression of CD152 and PD-1 on T lymphocytes and the expression of granzyme and perforin on CD152- and PD-1epositive CD8 T cells in peripheral blood were analyzed using flow cytometry. Results. The peripheral CD4/CD8 ratio in Gr-AR was significantly lower than that in Gr- SF (P < .01). The expression of CD152 and PD-1 on CD8 and CD4 T cells was significantly lower in Gr-AR than in Gr-SF (all P < .01). The expression of granzyme B and perforin was significantly higher in Gr-AR than in Gr-SF (P < .01). Conclusions. Down-regulation of the expression of negative costimulatory molecules such as CD152 and PD-1 on CD8 T cells may be associated with human acute liver allograft rejection.


Wang Y.,Peking University | Wang Y.,Research Center for Liver Transplantation | Zhang M.,Research Center for Liver Transplantation | Liu Z.-W.,Research Center for Liver Transplantation | And 9 more authors.
PLoS ONE | Year: 2014

CD4+CD25+FoxP3+ regulatory T cells (Tregs) and Th17 cells are known to be involved in the alloreactive responses in organ transplantation, but little is known about the relationship between Tregs and Th17 cells in the context of liver alloresponse. Here, we investigated whether the circulating Tregs/Th17 ratio is associated with acute allograft rejection in liver transplantation. In present study, thirty-eight patients who received liver transplant were enrolled. The patients were divided into two groups: acute allograft rejection group (Gr-AR) (n = 16) and stable allograft liver function group (Gr-SF) (n = 22). The frequencies of circulating Tregs and circulating Th17 cells, as well as Tregs/Th17 ratio were determined using flow cytometry. The association between Tregs/Th17 ratio and acute allograft rejection was then analyzed. Our results showed that the frequency of circulating Tregs was significantly decreased, whereas the frequency of circulating Th17 cells was significantly increased in liver allograft recipients who developed acute rejection. Tregs/Th17 ratio had a negative correlation with liver damage indices and the score of rejection activity index (RAI) after liver transplantation. In addition, the percentages of CTLA-4+, HLA-DR+, Ki67+, and IL-10+ Tregs were higher in Gr-SF group than in Gr-AR group. Our results suggested that the ratio of circulating Tregs/Th17 cells is associated with acute allograft rejection, thus the ratio may serve as an alternative marker for the diagnosis of acute rejection. © 2014 Wang et al.


Shi M.,Research Center for Liver Transplantation | Liu Z.-W.,Research Center for Liver Transplantation | Zhang Z.,Research Center for Biological Therapy | Wang F.-S.,Research Center for Biological Therapy
Medical Journal of Chinese People's Liberation Army | Year: 2013

Stem cells, including embryonic stem cells and adult stem cells, are multipotent cells that have self-renewing abilities and the potential to differentiate into various types of cells, and to repair various tissue damages. Bone marrow is the major source of adult stem cells, including mainly the bone marrow hematopoietic stem cells and mesenchymal stem cells. End-stage liver disease is a serious clinical systemic syndrome, and the use of stem cells in the treatment of end-stage liver disease has received more and more attention. This review summarizes the research progresses of stem cells, especially adult stem cells, in respect of the treatment of end-stage liver disease in the form of in vitro study, animal experimentation and clinical research, with emphasis on the research progress in the use of stem cells of various sources in clinical application, discussion of possible mechanisms of stem cell therapy for end-stage liver disease, to point out the problems existing in current research, and to look forward to the prospect of future application.


Shi M.,Institute of Translational Hepatology | Shi M.,Research Center for Liver Transplantation | Zhang Z.,Institute of Translational Hepatology | Xu R.,Institute of Translational Hepatology | And 12 more authors.
Stem Cells Translational Medicine | Year: 2012

Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cordderived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. © AlphaMed Press.

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