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Gao Y.,Liver Transplantation and Research Center | Zhang M.,Liver Transplantation and Research Center | Li J.,Liver Transplantation and Research Center | Yang M.,302 Military Hospital | And 5 more authors.
PLoS ONE | Year: 2015

Objective: To longitudinally investigate the role of FoxP3+ Regulatory T cells (Treg) and interleukin17- producing T helper 17 cells (Th17) in De Novo Hepatitis B Virus infection after orthotopic Liver Transplantation (DNHB-OLT), and analyze the possible correlation between these cells and HBV clearance of the disease. Methods: We enrolled 12 control cases after orthotopic Liver Transplantation (OLT) and 24 patients, including 12 diagnosed with DNHB-OLT and 12 diagnosed with Acute Hepatitis B Virus infection (AHB), into the study from the liver transplantation and research center at Beijing 302 Hospital. Flow cytometry was used to detect the frequencies of Treg and Th17, and ELISA was applied to detect the concentration of IL6, IL22, TGF-β and IL2 in peripheral blood. We also measured the gene expression level by real time-quantitative PCR and protein expression using immunohistochemistry and western-blot. Furthermore, we divided DNHB-OLT patients into the clearance and non-clearance groups and examined longitudinally Th17, Treg cells at different times. Results: The percentage of Treg cells, expression of FoxP3 mRNA and related anti-inflammatory cytokines such as IL2 and TGF-β1 in the DNHB-OLT group were significantly higher than that in the AHB and OLT groups. The percentage of Th17 cells, expression of RORγt mRNA and related pro-inflammatory cytokines such as IL17 and IL22 in the DNHB-OLT group were significantly lower than that in the AHB group, but the levels of these cytokines are very similar to the OLT group. The ratios of Treg to Th17 in the DNHB-OLT group were significantly higher than that in the OLT and AHB groups. Treg frequencies significantly correlated with HBV DNA, whereas IL17 frequencies didn't significantly correlate with ALT. In DNHB-OLT patients, the clearance group was accompanied by a rapid increase in the Th17 cells during the first 4th week and afterwards continuously decrease to the control group, together with a continuously decrease in Treg cells from the onset time point, which lead to a significant reduction in the ratios of Treg to Th17. The non-clearance group was accompanied by an increase in the Treg cells during the first 4th week and afterwards sharply decrease, together with a relatively stable and unchanged Th17 cells, which lead to a significant change in the ratios. In addition, compared to clearance group, the ratios of Treg to Th17 in non-clearance group were significantly higher at the onset point, 4th and 12th week, but no difference at 24th week. Conclusion: DNHB-OLT patients possessed a favorable Treg differentiation environment, accompanied by a sustained higher preferentially Treg frequencies and up-regulation of related antiinflammatory cytokines. The immune imbalance of the ratios between Treg and Th17 existed in DNHB-OLT patients. The changes of the ratios during the DNHB-OLT events were associated with HBV clearance, which suppressed immune inflammation reaction as well as inhibited ability of specific HBV clearance and led to immune escape and chronicity. © 2015 Gao et al. Source


Ozsoy M.,Afyon Kocatepe University | Unalp O.V.,Ege University | Sozbilen M.,Ege University | Alper M.,Liver Transplantation and Research Center | And 2 more authors.
Transplantation Proceedings | Year: 2014

Background Living donor liver transplantation has been a new light of hope for patients with end-stage liver failure on the cadaveric waiting list. However, living donor liver transplantation still has ethical problems which cannot be overcome. Exposure of healthy donor candidates to major surgery which can be fatal is the largest of these ethical problems. In this study, we aimed to determine our rate of complications associated with surgery in donors who underwent right lobe donor hepatectomy. Materials and Methods Between September 2004 and December 2009, 548 liver donor candidates were examined. The right liver lobe donor hepatectomy was performed on 272 donor candidates who passed the elimination system. Demographic data as well as intraoperative findings, complication rates, and numbers were collected retrospectively. Donor complications were categorized according to the Clavien classification. Results Two hundred seventy-two donors who underwent right lobe donor hepatectomy were included in this study. One hundred sixteen (42.6%) of 272 donors were female, whereas 156 (57.4%) were male. There was no donor mortality. Grade 1 and grade 2 complications were observed in 105 (38%) of 272 donors. The most common complications were fever of unknown origin (20.9%) and prolonged hyperbilirubinemia (3.6%). Grade 3 complications and grade 4 complications were observed in 6 donors (2%) and 3 donors (1%), respectively. Three donors were underwent re-operation due to bleeding. The re-laparatomy rate in our series was detected as 1.10%. One donor, categorized as grade 4B according to the Clavien classification, had small bowel perforation and intra-abdominal sepsis secondary to mechanical bowel obstruction. Conclusions Donor mortality is a fact of living donor liver transplantation that cannot be ignored like donor morbidity. However, right liver lobe donor hepatectomy can be performed successfully with minimal complication rates with multidisciplinary and rigorous donor care in the preoperative and postoperative period. © 2014 by Elsevier Inc. All rights reserved. Source


Gao Y.,Liver Transplantation and Research Center | Ren H.,Liver Transplantation and Research Center | Meng F.,Liver Cirrhosis and Research Center | Li J.,Liver Transplantation and Research Center | And 7 more authors.
PLoS ONE | Year: 2016

Objective: The aim of this study was to longitudinally evaluate and analyze the role of interleukin-22-producing CD4 positive cells (IL-22) in the pathogenesis of Hepatitis C Virus recurrence after Orthotopic Liver Transplantation (HCV-OLT). Methods: 15 HCV-OLT, 15 age- and gender- matched non-HCV post-OLT (OLT) and 15 hepatitis C virus infected (HCV) patients were enrolled into our study from the liver transplantation and research center at Beijing 302 Hospital. We determined the frequencies of IL-22 using flow cytometry and expression of IL-22 mRNA using PCR in peripheral blood and liver tissue. We also divided HCV-OLT patients into rapid fibrosis progression (RFP) and slow fibrosis progression (SFP), examined IL-22 cells and analyzed the correlations between IL-22 frequencies and liver injury, fibrosis and clinical parameters. Moreover, we investigated the role of IL-22 in Human Hepatic Stellate Cells (HSCs). Results: The levels of serum IL-22, frequencies of IL-22 producing cells in peripheral blood mononuclear cells, and expression of IL-22 mRNA and protein in the liver in the HCV-OLT group were significantly higher than that in the HCV and OLT groups. Furthermore, eight (53.3%) patients developed RFP after two years; another three patients were diagnosed liver cirrhosis. The frequencies of IL-22 were much higher in RFP compared with SFP, while no significant difference existed between OLT and SFP. Intrahepatic IL-22 positive cells were located in fibrotic areas and significantly correlated with α-smooth muscle actin (α-SMA) and fibrosis staging scores, not with grading scores and HCRVNA. In vitro, IL-22 administration prevented HSCs apoptosis, promoted HSCs proliferation and activation, upregulated the expression of HSC-sourced growth factors including α-SMA, TGF-β and TIMP-1, and increased the production of liver fibrosis markers including laminin, hyaluronic acid and collagen type IV. Conclusion: Peripheral and intrahepatic IL-22 is up-regulated and plays a pathological role in exacerbating liver fibrosis by activating HSCs in HCV-OLT patients, which may predict RFP and serve as an attractive target for anti-fibrotic therapy. © 2016 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

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