S. Zheng

Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B Immunoglobulin prophylaxis.

The aim of our study was to determine the outcomes of liver transplant recipients receiving either lamivudine (LAM) monotherapy or LAM combined with low‐dose intramuscular (IM) hepatitis B Immunoglobulin (HBIG) therapy. We performed a retrospective review of the medical records of patients that had had liver transplantation in a single center for HBV‐related liver diseases from December 1999 to June 2004. A total of 165 patients received LAM monotherapy (51 patients) or combined prophylaxis (114 patients) post‐liver transplantation (LT) with a mean follow‐up of 20.13 months. Hepatitis B relapsed in 21 patients of the hepatitis B surface antigen (HBsAg) carriers who received LAM monotherapy, with a 1‐ and 2‐yr actuarial risk of 27.4% and 39.7%. Recurrence occurred in 16 patients of 114 patients receiving the combined prophylaxis, with a 1‐ and 2‐yr recurrence rate of 13.5% and 15.2% (P= 0.024). A total of 25 cases (67.6%) with YMDD mutants were detected in all the 37 patients, 14 cases (66.7%) in the monotherapy group and 11 cases (68.8%) in the combination group. In conclusion, LAM and low‐dose intramuscular HBIG treatment demonstrates a better result than LAM monotherapy, as prophylaxis against post‐LT reinfection of the graft, but the safety and efficacy as a substitution for high‐dose intravenous HBIG with LAM needs to be investigated further. Liver Transpl 12:253–258, 2006.

Multidrug resistant gram-negative bacilli as predominant bacteremic pathogens in liver transplant recipients.

Background. Bacteremias, which are often caused by gram‐negative bacteria, are the most frequently occurring infectious complications after liver transplantation (LT). The aim of this study was to investigate bacteremic incidence, pathogenic spectrum, risk factors for bacteremia due to multidrug resistant (MDR) gram‐negative bacilli, and its impact on mortality after LT.

Bone Marrow–Derived Mesenchymal Stem Cells Inhibit Acute Rejection of Rat Liver Allografts in Association With Regulatory T-Cell Expansion

Bone marrow-derived mesenchymal stem cells (MSCs) exhibit immunosuppressive functions in vitro and in vivo. We investigated the immunoregulatory effects of rat MSCs in a model of allogeneic liver transplantation. Brown Norway rats received livers from inbred Lewis rats, and at designated intervals, infusions of MSCs derived from recipient, donor, or third-party rats. Allograft rejection and recipient survival rates were recorded. In particular, changes in circulating regulatory T cells (Tregs) were measured. After administration of MSCs derived from each of the 3 strains, allograft recipients demonstrated markedly longer survival compared with control animals. Histologic analysis revealed significant inhibition of allograft rejection. The MSCs induced generation of CD4+CD25+Foxp3+ Tregs. We concluded that MSCs inhibit acute rejection of allografts after liver transplantation, and propose that the immunoregulatory effects of MSCs are associated with expansion of Tregs.

Liver Regeneration after Liver Transplantation

Background/Purpose: The liver has a remarkable capacity to regenerate after injury or resection. The aim of this review is to outline the mechanisms and factors affecting liver regeneration after liver transplantation. Methods: Relevant studies were reviewed using Medline, PubMed and Springer databases. Results: A variety of cytokines (such as interleukin-6 and tumor necrosis factor-α), growth factors (like hepatocyte growth factor and transforming growth factor-α) and cells are involved in liver regeneration. Several factors affect liver regeneration after transplantation such as ischemic injury, graft size, immunosuppression, steatosis, donor age and viral hepatitis. Conclusion: Liver regeneration has been studied for many years. However, further research is essential to reveal the complex processes affecting liver regeneration, which may provide novel strategies in the management of liver transplantation recipients and donors.

Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantation

L. Zhou, B. Wei, C. Xing, H. Xie, X. Yu, L. Wu, S. Zheng. Polymorphism in 3′‐untranslated region of toll‐like receptor 4 gene is associated with protection from hepatitis B virus recurrence after liver transplantationu2028Transpl Infect Dis 2011: 13: 250–258. All rights reserved

Activation pattern of mitogen-activated protein kinases in early phase of different size liver isografts in rats.

Mitogen‐activated protein kinases (MAPK) play a pivotal role in ischemia reperfusion injuries of heart and liver, but the activation pattern of MAPKs in the early phase of different size liver isografts remains unclear. The experiment is designed to investigate the activation pattern and role of MAPKs in isografts of the rat with different size liver transplantation. The animal models of different size graft liver transplantation (whole graft, 50% size, or 30% size, respectively) were established and the sham operation group served as a control. The recipients were sacrificed at 0.5‐, 2‐, 6‐, and 24‐hour time points after transplantation to harvest the graft specimens and blood samples. The serum aspartate amino transferase (AST), alanine amino transferase (ALT) and tumor necrosis factor‐α (TNF‐α) levels, and histological findings were evaluated. The expressions of the total and phosphorylated p46/p54 JNKs, p38 MAPK, and p42/p44 ERKs were detected by Western blot. The serum ALT and AST levels increased significantly at the 0.5‐hour time point and maintained high with the peak levels at the 6‐hour time point after liver transplantation. The different sizes of liver isografts did not change the expressions of total p46/p54JNKs, p38MAPK, and p42/p44 ERKs. While the expressions of phosphorylated p46/p54JNKs, p38 MAPK, and p42/p44 ERKs were either negative or mildly up‐regulated in the sham operation group, they were significantly activated in the transplanted liver at the 0.5‐hour time point, especially in the 30% size liver transplantation group. In conclusion, the activation of three MAPKs in liver isografts correlates with graft size and the JNK and p38 MAPK are responsible for the graft injury while the ERK signal pathway maybe participate in the regulation of cell growth and differentiation after small‐for‐size liver transplantation. (Liver Transpl 2005;11:1527–1532.)

Primary Hepatic Carcinoid Tumours: Clinical Features with an Emphasis on Carcinoid Syndrome and Recurrence

This study sought to determine the clinical profiles and optimal management of primary hepatic carcinoid tumours. The clinical features of nine Chinese patients and 64 patients reported in the English-language literature were characterized. Recurrence rate and survival analysis were performed with the Kaplan–Meier method. The impact of surgical resection and post-operative recurrence on survival was determined by means of the log-rank test. Carcinoid syndrome complicated 10 cases (14%). Sixty-two patients (85%) underwent surgical resection. Actuarial 5-and 10-year survival rates for resected patients were 80% and 75%, respectively. Twelve patients experienced recurrences: the recurrence rate at 5 years post-operatively was 26%. All patients with resectable recurrent disease achieved good long-term survival and no significant relationship was found between recurrence and survival. Owing to the high incidence of recurrence, long-term follow-up is necessary and it is recommended that recurrent cases should be managed with judicious surgical resection.

Antiproliferative and Overadditive Effects of Rapamycin and FTY720 in Pancreatic Cancer Cells In Vitro

UNLABELLEDnRapamycin inhibits the growth of several tumors including pancreatic carcinoma both in vitro and in vivo. The antitumor effects of FTY720 were also shown recently. The present study was performed to investigate the in vitro antiproliferative capacity of combined treatment with rapamycin and FTY720 on pancreatic cacinoma cell lines.nnnMATERIALS AND METHODSnThe Panc-1 and AsPc-1 cell lines were employed as the pancreatic carcinoma model in vitro. For monotreatment experiments, rapamycin was added in increasing doses from 0.002 micromol/L to 200 micromol/L; FTY720 was used from 1 micromol/L to 15 micromol/L. For combined treatment, two concentrations of rapamycin were combined with seven concentrations of FTY720; or two concentrations of FTY720 with five concentrations of rapamycin. The antiproliferative capacity was assessed by the MTT assay.nnnRESULTSnRapamycin and FTY720 inhibited MTT incorporation into Panc-1 and AsPc-1 in dose-dependent fashion with or without serum stimulation. In coincubation experiments, great susceptibility to rapamycin was seen when combined with 10 micromol/L FTY720. An effective combination for AsPc-1 was 10 micromol/L FTY720 with 0.002 micromol/L rapamycin, resulting in more than 50% inhibition of MTT incorporation, and for Panc-1, 10 micromol/L FTY720 with 0.002 micromol/L rapamycin and 10 micromol/L FTY720 with 20 micromol/L rapamycin; the corresponding inhibition levels reached about 40% and 60%, respectively.nnnCONCLUSIONnRapamycin and FTY720 showed dose-dependent antiproliferative effects on pancreatic carcinoma cell lines in vitro both alone and in combination. The combined use of rapamycin and FTY720 showed additive and supra-additive antiproliferative effects on pancreatic carcinoma cell lines. The susceptibility of pancreatic carcinoma cells to rapamycin was significantly enhanced when combined with FTY720.

Galectin-1 prolongs survival of mouse liver allografts from Flt3L-pretreated donors.

Liver allografts are spontaneously accepted across MHC barriers in mice. The mechanisms underlying this phenomenon remain poorly understood. Galectin‐1, an endogenous lectin expressed in lymphoid organs, plays a vital role in maintaining central and peripheral tolerance. This study was to investigate the role of galectin‐1 in spontaneous tolerance of liver allografts in mice, and to evaluate the therapeutic effects of galectin‐1 on liver allograft rejection induced by donor Flt3L pretreatment. Blockade of the galectin‐1 pathway via neutralizing antigalectin‐1 mAb did not affect survival of the liver allografts from B6 donors into C3H recipients. Administration of rGal‐1 significantly prolonged survival of liver allografts from Flt3L‐pretreated donors and ameliorated Flt3L‐triggered liver allograft rejection. This effect was associated with increased apoptosis of T cells in both allografts and spleens, decreased frequencies of Th1 and Th17 cells, decreased expression of Th1‐associated cytokines (IL‐12, IL‐2 and IFN‐γ), Th17‐associated cytokines (IL‐23 and IL‐17) and granzyme B, in parallel with selectively increased IL‐10 expression in liver allografts. In vitro, galectin‐1 inhibited Flt3L‐differentiated DC‐mediated proliferation of allo‐CD4+ T cells and production of IFN‐γ and IL‐17. These data provide new evidence of the potential regulatory effects of galectin‐1 in alloimmune responses in a murine model of liver transplantation.

Proteomic analysis of differentially expressed proteins in rat liver allografts developed acute rejection.

Background: Acute rejection (AR) after liver transplantation is a cell-mediated immune response that takes place within the allograft and results in graft dysfunction and failure, but the molecular mechanisms about hepatocyte dysfunction remain poorly understood. Here we characterized global protein expression changes in liver allograft during AR. Methods: The effect of an alloantigen-dependent immunological response was evaluated by syngeneic and allogeneic rat orthotopic liver transplantation (OLT). Using a combination of two-dimensional gel electrophoresis and mass spectrometry, we identified 18 differentially expressed proteins in AR allograft compared with matched tolerance allograft. Serum chemistry and allograft histology were determined. Results: Allogeneic OLT recipients exhibited elevated plasma levels of liver injury markers, progressive portal and venous inflammation and cellular infiltration in liver allograft compared with syngeneic OLT. 18 protein expressions altered by AR play important roles in metabolism, oxidative stress defense, signal transduction, biotransformation and transport. Decreased expression of protein disulfide isomerase in AR allograft was confirmed by Western blotting and immunohistochemistry. Conclusions: This study uncovered new mechanistic insights into graft dysfunction in AR of liver allograft. Several significantly altered protein expressions act coordinately in hepatocyte dysfunction by depressed energy, enhanced oxidative stress-induced molecular damage and restrained biotransformation. The present findings may open new avenues for the understanding and prevention of graft dysfunction and failure during AR.