Search

• The donor-derived imDCs has the potent in mediating antigen-specific immunotolerance. • Donor-derived imDCs prolonged allograft survival by increasing the content of Tregs. • Inducing donor-specific CD8+Tregs modified by tolDCs derived from BM-MSCs may a new direction to break through immune tolerance induction. • Rapa modified tolDCs reversed graft rejection by improve tolerance characteristics of CD8+CD45RC−Treg in a rat acute LT. To investigate the influence of tolerance dendritic cells (tolDCs), generated from Bone marrow mesenchymal stem cells (BM-MSCs) treated with rapamycin (Rapa) on liver allograft survival in a rat acute liver transplantation model. Different GM-CSF induction project was used to obtain immature DCs (imDCs), mature DCs (matDCs) or tolDCs from BM-MSCs. First, MLR was performed to analyze the activity of tolDCs on polyclonaly stimulated total T cells. Then, co-cultured imDCs, matDCs and tolDCs with CD8+T cells isolated by magnetic activated cell sorting to analyze the influence on its regulatory characteristic. Last, the established rat acute liver transplantation model were adoptive transfused with imDCs, matDCs or tolDCs isolated by anti-CD11c immunomagnetic beads. The phenotype of DC cells and level of CD8+Treg in the culture system and in vivo, the expression of CD8 and CD45RC in the tissues were analyzed by flow cytometry and immunohistochemistry, respectively. The loGM-CSF plus IL-4 decreased the costimulatory molecules of CD80/86 and MHC class II of DCs comparison with hiGM-CSF from BM-MSCs no matter whether stimulation by LPS (P<0.05). Rapa treated not only reduced the expression of CD80/86 and MHC class II but also down-regulated the expression of CD11c after LPS stimulation which was more obviously in tolDCs by loGM-CSF project (P<0.05). Moreover, tolDCs displayed a rather higher level of IL-10 and low level of IL-12p70 than others (P<0.01), which shown a rather lower stimulative effect on the proliferation of T cells comparison with matDCs and imDCs. Co-cultured with CD8+Treg showed an improvement on induction of CD8+TCR+CD45RC−T cells (CD8+Treg) in ex vivo. The rats transfused with tolDCs has a delayed survival benefits with high level of CD8+Tregs (P<0.01) and high expression of CD45RC in liver tissue (P<0.01) and spleen when comparison with other groups. The infused tolDCs improved a mean survival time (MST) of 32 days comparison with a MTS of 9.5 days and 15.75 days displayed by rat that per-infused with matDCs and imDCs, respectively. Rapa modified tolDCs derived from BM-MSCs reversed graft rejection by improve tolerance characteristics of CD8+CD45RC−Treg in acute liver rat transplantation. [ABSTRACT FROM AUTHOR]

Although liver transplantation (LT) lengthens the survival time of patients with hepatocellular carcinoma (HCC), LT patients exhibit a high recurrence rate; particularly those that had advanced HCC associated with the tumor biological characteristics and long‑term application of immunosuppressants. A consensus on optimal prophylaxis and treatment for recurrent HCC following LT does not currently exist. The present study retrospectively analyzed data from 36 non‑University of California at San Francisco criteria‑eligible patients with advanced HCC who underwent LT, and then treated them with sirolimus (SRL)‑based therapy with thymalfasin and huaier granules (SRL+, n=18), or with tacrolimus‑based therapy (controls; n=18). The SRL+ group had significantly longer recurrence times (P=0.008) and survival times (P<0.0001) (OS, 1‑year: 100%, 3‑year: 94.4%, 5‑year: 77.8%; DFS, 1‑year: 88.9%, 3‑year: 55.6%, 5‑year: 50.0%). Furthermore, compared with pre‑LT values and the control group, the SRL+ group had significantly lower serum α‑fetoprotein (AFP) levels (both P<0.0001) and percentage of Forkhead box P3 (FoxP3)+ Treg lymphocytes (P<0.001) during the first year. In the SRL+ group, FoxP3+/cluster of differentiation (CD)8+ Treg lymphocyte percentages decreased significantly following LT (P<0.001); however, CD8+/CD3+ T‑cells significantly increased (P<0.001). Levels of serum AFP and FoxP3+ Treg cells increased when tumors relapsed, and decreased to near‑normal when relapse foci were cured or stabilized. SRL+ therapy may decrease AFP and Treg levels, while increasing CD8+ T cells, indicating an associated mechanism among them. In conclusion, SRL+ therapy appears to be safe and effective in preventing HCC recurrence following LT with no significant adverse events, and warrants further investigation. [ABSTRACT FROM AUTHOR]

Tolerance is more easily induced in liver transplant models than in other organs; CD8+CD45RClowregulatory T cells (Tregs) have been shown to induce tolerance in heart allografts. Whether CD8+CD45RClowTregs could induce tolerance in a liver transplant model and how dendritic cells (DCs) mediate the CD8+CD45RClowTregs effect remains to be investigated. A rat liver transplantation model was established and used to test tolerance and acute rejection compared to control groups. Liver function and histopathological changes of allograft were examined by enzyme-linked immunosorbent assay (ELISA) and haematoxylin and eosin (H&E) staining, respectively. The distribution and proportion of CD8+CD45RClowTregs and plasmacytoid dendritic cells (pDCs) in the allografts and spleen were determined using flow cytometry. Cytokine secretion levels were determined using ELISA and real-time quantitative PCR (qRT-PCR). The rat liver transplantation model was well established, with a success rate of 93.3% (28/30). The mean survival time of the tolerant and acute-rejection rats were 156 and 14 days, respectively. The proportions of CD8+CD45RClowTegs were higher in the allografts of tolerant rats than in those of acute-rejection rats (33.1 ± 4.3 and 12.4 ± 4.6, respectively; P = 0.04). Significant accumulation of pDCs was observed in tolerant liver graft rats compared to that in acute-rejection rats (1.46 ± 0.23 and 0.80 ± 0.20, respectively; P = 0.02). Importantly, CD8+CD45RClowTregs were positively associated with the frequency of pDCs (P = 0.001, r2 = 0.775). The protein and mRNA expression of IL-10 and TGF-β in the allograft group were increased, possibly being responsible for tolerance induction. CD8+CD45RClowT cells interact with pDCs through the induction of IL-10 and TGF-β expression and are responsible for inducing immune tolerance in rat liver transplantation. • Immune tolerance induction is of great significance to transplant recipients. • CD8+Tregs have a powerful function of inducing immune tolerance. • CD8+Tregs induce the rat liver transplantation tolerance by interacting with pDCs. • CD8+CD45RClowTregs and pDCs are therapeutic potential in anti-transplant rejection. [ABSTRACT FROM AUTHOR]

Background: The most effective treatment for end-stage liver diseases is liver transplantation, which is impeded by the shortage of donor livers. Split liver transplantation (SLT) is important for addressing the donor liver shortage. However, full-right full-left SLT for two adult recipients is globally rarely conducted. This study aimed to investigate the clinical outcomes of this technique. Methods: We retrospectively analyzed the clinical data of 22 recipients who underwent full-right full-left SLT at Shulan (Hangzhou) Hospital between January, 2021 and September, 2022. The graft-to-recipient weight ratio (GRWR), cold ischemia time, operation time, length of the anhepatic phase, intraoperative blood loss, and red blood cell transfusion amount were all analyzed. The differences in liver function recovery after transplantation were compared between the left and right hemiliver groups. The postoperative complications and prognosis of the recipients were also analyzed. Results: The livers of 11 donors were transplanted into 22 adult recipients. The GRWR ranged from 1.16–1.65%, the cold ischemia time was 282.86 ± 134.87 min, the operation time was 371.32 ± 75.36 min, the anhepatic phase lasted 60.73 ± 19.00 min, the intraoperative blood loss was 759.09 ± 316.84 mL, and the red blood cell transfusion amount was 695.45 ± 393.67 mL. No significant difference in the levels of liver function markers, total bilirubin, aspartate aminotransferase, or alanine aminotransferase between left and right hemiliver groups at 1, 3, 5, 7, 14, and 28 d postoperatively was observed (both p > 0.05). One recipient developed bile leakage 10 d after transplantation, which improved with endoscopic retrograde cholangiopancreatography-guided nasobiliary drainage and stent placement. Another developed portal vein thrombosis 12 d after transplantation and underwent portal vein thrombectomy and stenting to restore portal vein blood flow. A color Doppler ultrasound performed 2 d after transplantation revealed hepatic artery thrombosis in one patient, and thrombolytic therapy was administered to restore hepatic artery blood flow. The liver function of other patients recovered quickly after transplantation. Conclusions: Full-right full-left SLT for two adult patients is an efficient way to increase the donor pool. It is safe and feasible with careful donor and recipient selection. Transplant hospitals with highly experienced surgeons in SLT are recommended to promote using full-right full-left SLT for two adult recipients. [ABSTRACT FROM AUTHOR]

Figures and Table Graph: Figure 1 (A) The hepatic veins of Segments V and VIII were retained in the right hemiliver and reconstructed with iliac artery. (B) The retrohepatic inferior vena cava (IVC) was divided by longitudinal transection of the front and back walls. (D) Reconstruction of the MHV and IVC in the left hemiliver graft. [Extracted from the article]

To investigate the molecular impact of graft MaS on post-transplant prognosis, based on multi-omics integrative analysis. Rats were fed by methionine-choline deficient diet (MCD) for MaS grafts. Samples were collected from grafts by sequential biopsies. Transcriptomic and metabolomic profilings were assayed. Post-transplant MaS status showed a close association with graft failure. Differentially expressed genes (DEGs) for in-vivo MaS were mainly enriched on pathways of cell cycle and DNA replication. Post-transplant MaS caused arrests of graft regeneration via inhibiting the E2F1 centered network, which was confirmed by an in vitro experiment. Data from metabolomics assays found insufficient serine/creatine which is located on one‑carbon metabolism was responsible for MaS-related GF. Pre-transplant MaS caused severe fibrosis in long-term survivors. DEGs for grafts from long-term survivors with pre-transplant MaS were mainly enriched in pathways of ECM-receptor interaction and focal adhesion. Transcriptional regulatory network analysis confirmed SOX9 as a key transcription factor (TF) for MaS-related fibrosis. Metabolomic assays found elevation of aromatic amino acid (AAA) was a major feature of fibrosis in long-term survivors. Graft MaS in vivo increased post-transplant GF via negative regulations on graft regeneration. Pre-transplant MaS induced severe fibrosis in long-term survivors via activations on ECM-receptor interaction and AAA metabolism. • MaS in vivo affects postoperative survival status for rats LT receivors; • MaS caused GF via suppressed regeneration E2F1 centered TRN; • Pre-transplant MaS causes fibrosis in long-term survivors via SOX9 centered TRN. [ABSTRACT FROM AUTHOR]

MicroRNA‑424 (miR‑424) has previously been described as a biomarker of poor prognosis in patients with hepatocellular carcinoma (HCC). In the present study, the clinical significance of miR‑424 expression in predicting the rate of tumor recurrence in patients with HCC following liver transplantation (LT) was evaluated. miR‑424 expression in HCC samples from 121 patients undergoing LT was examined, and the associations between clinical parameters and patient tumor recurrence were evaluated. The miR‑424 expression level in cancer tissues was low compared with that in adjacent noncancerous tissues. Multivariate analyses revealed that low miR‑424 expression was an independent prognostic factor for tumor recurrence in patients with HCC following liver transplantation. Patients who no longer met the Milan criteria and had decreased miR‑424 expression levels exhibited earlier tumor recurrence following LT. In addition, the upregulation of miR‑424 expression significantly reduced the migration, invasion and proliferation of HCC cells. Similarly, the downregulation of miR‑424 in HCC cells significantly promoted the migration, invasion and proliferation of HCC cells. [ABSTRACT FROM AUTHOR]

TFCP2 is an oncogene and plays crucial roles in the incidence and progression of hepatocellular carcinoma (HCC). However, no reports are available on the impact of TFCP2 genetic polymorphism on the susceptibility to and the transplant prognosis of HCC. Here, we genotyped 7 SNPs of TFCP2 in a case-control study of 119 patients with HCC and 200 patients with chronic liver disease. Of the 7 SNPs in TFCP2, rs7959378 distributed differentially between patients with versus patients without HCC. The patients with the CA (OR = 0.58, 95% CI = 0.35–0.96), the CC (OR = 0.39, 95% CI = 0.20–0.76), and the CA/CC (OR = 0.52, 95% CI = 0.32–0.83) genotypes had significantly decreased risk for HCC compared with those carrying the rs7959378 AA genotype. After adjusting for confounding factors, rs7959378 still conferred significant risk for HCC. Furthermore, the patients who carried rs7959378 AC/CC had a higher overall survival and lower relapse-free survival than those with the rs7959378 AA genotype. Similar results were found in the multivariate analysis adjusted by AFP, tumor size and tumor number, and differentiation. These findings indicate that rs7959378 is associated with the risk of HCC in patient with chronic liver disease and prognosis of HCC patients after liver transplantation. [ABSTRACT FROM AUTHOR]

Aim Neutrophil to lymphocyte ratio (NLR) is an inflammatory biomarker that has a close relationship with tumor progression and metastasis. In this study, we aimed to investigate the role of NLR in the prognosis of male candidates with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). Methods We analyzed the clinical data of 248 male HCC candidates who underwent LT in our Liver Transplantation Center between 2002 and 2012. All risk factors were analyzed by univariate and multivariate Cox analysis and survival rates were calculated by Kaplan-Meier log-rank test. Results NLR was proved to be an independent risk factor affecting overall survival (OS) ( P < 0.001) and tumor-free survival (TFS) ( P = 0.003) of male candidates with HCC following LT. Additionally, our study showed that elevated NLR (>4) was associated with early tumor recurrence by Kaplan-Meier analysis. Furthermore, we established Model_OS and Model_TFS to predict prognosis based on multivariate Cox analysis. Our study showed that male candidates with HCC who exceeded the Milan criteria but within Model_OS could achieve similar OS as those within the Milan criteria ( P = 0.220). Similarly, male patients who exceeded the Milan criteria but within Model_TFS could achieve similar TFS as those within the Milan criteria ( P = 0.197). Conclusion Proper inflammatory response may effectively reduce tumor recurrence after LT. Elevated NLR (>4) within a certain range is associated with early tumor recurrence. NLR-based models are efficient and safe for prognostic prediction among male candidates with HCC for LT. [ABSTRACT FROM AUTHOR]

Background and Aims Absolute lymphocyte count ( ALC) and the recovery of ALC after treatment have been identified as a prognostic biomarker for several malignancies. In this study, we aimed to investigate the prognostic role of peritransplant ALC and ALC recovery after liver transplantation ( LT) in hepatocellular carcinoma ( HCC) patients. Methods A total of 269 HCC patients undergoing LT were enrolled in our study. Clinicopathological data were retrospectively collected and reviewed. Peritransplant ALC and the change of ALC (2 weeks, 1 month, 3 months post- LT) were carefully monitored. All potential risk factors were analyzed by univariate and multivariate cox regression analysis. Results Over a mean follow-up of 35.9 months, 120 recurrences and 89 deaths were recorded. In the multivariate analysis, HCC with ALC no recovery at 1 month after LT ( P < 0.001), high pretransplant alpha fetoprotein ( P = 0.010), total tumor size > 8 cm ( P = 0.003), and beyond Milan criteria ( P < 0.001) were four independent risk factors for HCC recurrence. For overall survival ( OS) after LT, ALC no recovery at 1 month after LT ( P = 0.003), total tumor size > 8 cm ( P = 0.011), pretransplant albumin < 2.8 g/dL ( P = 0.049), model of end-stage liver disease score > 15 ( P = 0.017), and beyond Milan criteria ( P = 0.001) were significantly related to poor OS. When subgroup analyses were performed according to the Milan criteria, the results showed that the recovery of ALC at 1 month after LT still indicated longer recurrence-free survival ( RFS) ( P < 0.001) and OS ( P = 0.005) beyond Milan criteria as well as RFS ( P < 0.001) within Milan criteria, but not OS ( P = 0.157) within Milan criteria. Conclusions ALC recovery at 1 month after LT indicated favorable outcomes of HCC patients. [ABSTRACT FROM AUTHOR]

Background/Aim: Liver transplantation is a well-recognized treatment for non-resectable hepatocellular carcinoma (HCC); however, the overall survival and waiting list removal rates for hepatitis C virus (HCV)-related HCC have not been assessed. Methods: The present study included 11,146 patients with HCC and 64,788 patients without HCC, listed for liver transplantation on the Scientific Registry of Transplant Recipients database between 2003 and 2010. Results: In a multivariate analysis, HCV infection was an independent predictor of being transplanted or remaining on the waiting list in HCC candidates (HR 0.65, 95 % CI 0.60-0.71, p < 0.001). However, patients in the advanced status (model for end-stage liver disease score over 20, tumor stage exceed tumor-node-metastasis stage II, or alpha fetoprotein lover 400 ng/ml) but without HCV had better post-transplant survival than patients in the advanced status and with HCV (64 vs. 47 % at 5 years, p < 0.001), and comparable survival to patients with HCV but not in the advanced status (62 %, p = 0.461). Conclusions: HCC candidates with HCV infection are more likely to be transplanted, remain on the waiting list for longer, and have worse post-transplant survival. Patients in the advanced status but without HCV also could share a similar post-transplant survival to those not in the advanced status but with HCV. [ABSTRACT FROM AUTHOR]

Spontaneous immune tolerance in mouse liver transplantation has always been a hotspot in transplantation-immune research. Recent studies revealed that regulatory T cells (Tregs), hepatic satellite cells and Kupffer cells play a potential role in spontaneous immune tolerance, however the precise mechanism of spontaneous immune tolerance is still undefined. By using Microarray Chips, we investigated different immune regulatory factors to decipher critical mechanisms of spontaneous tolerance after mouse liver transplantation. Allogeneic (C57BL/6-C3H) and syngeneic (C3H-C3H) liver transplantation were performed by 6-8 weeks old male C57BL/6 and C3H mice. Graft samples (N = 4 each group) were collected from 8 weeks post-operation mice. 11 differentially expressed miRNAs in allogeneic grafts (Allografts) vs. syngeneic grafts (Syngrafts) were identified using Agilent Mouse miRNA Chips. It was revealed that 185 genes were modified by the 11 miRNAs, furthermore, within the 185 target genes, 11 of them were tightly correlated with immune regulation after Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Genbank data cross-comparison. Verified by real-time PCR and western blot, our results indicated that mRNA expression levels of IL-6 and TAB2 were respectively down regulated following miR-142-3p and miR-155 augment. In addition, increased miR-152 just silenced mRNA of CaMK II and down-regulated translation of CaMK II in tolerated liver grafts, which may play a critical role in immune regulation and spontaneous tolerance induction of mouse liver transplantation. [ABSTRACT FROM AUTHOR]

Summary Mucormycosis is a rare but potentially lethal complication of liver transplantation. Most reported cases have involved rhinocerebral, pulmonary, gastrointestinal, or disseminated forms. We present herein the case of a 61-year-old male patient with hepatocellular carcinoma who developed isolated penile mucormycosis after orthotopic liver transplantation. Such a case has not been reported in the literature to date. Early diagnosis and timely surgical intervention combined with comprehensive treatment are the key factors for improving the survival rate in patients with mucormycosis. [ABSTRACT FROM AUTHOR]

• We provided the first experimental evidence of a therapeutic role for galectin-1 in attenuating hepatic IRI via an IL-10-dependent Manner. • Galectin-1 treatment significantly attenuated hepatic IRI, as evidenced by a significant reduction in serum ALT/AST levels, an improved liver histology score and the number of TUNEL positive apoptotic hepatocytes, compared with controls. • Galectin-1 treatment elicited an altered inflammation response, with reduced gene induction of pro-inflammatory cytokines/chemokines, and concomitant preserved anti-inflammatory IL-10 formation. • Blockade of IL-10 recreated hepatic IRI in rGal-1-treated mice. Hepatic ischemia reperfusion injury (IRI) is a primary cause of organ dysfunction occurring during liver resection surgery and transplantation. Galectin-1, an endogenous lectin expressed on lymphoid organs, plays an important role in governing innate and adaptive immunity. This study was designed to determine the therapeutic role of galectin-1 and underlying mechanism in hepatic IRI. Male C57BL/6 mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion with or without treatment with recombinant galectin-1 (rGal-1) or neutralizing anti-IL-10 antibody. Mice were sacrificed at 6 and 24 h following reperfusion. Liver damage related enzymes were determined and cytokines/chemokines were measured by qPCR and ELISA. Administration of rGal-1 significantly attenuated hepatic IRI, including a remarkable reduction in serum ALT/AST levels and an improved liver histology score compared to controls. rGal-1 treatment reduced TUNEL positive apoptotic hepatocytes, attenuated proinflammatory cytokines (TNF-α, IL-6, IL-1β, IL-12, IFN-γ, IL-17) and chemokines (CXCL-1, CXCL-10) levels, but upregulated IL-10 expression, compared with controls. In addition, rGal-1 increased the production of IL-10 in hepatic macrophages in vivo and in vitro. Blockade of IL-10 using neutralizing anti-IL-10 antibody reversed the protection of galectin-1 in hepatic IRI in mice. These data suggest that galectin-1 may attenuate hepatic IRI via an IL-10-dependent mechanism, which is a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Early recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is associated with poor surgical outcomes. This study aims to construct a preoperative model to predict individual risk of post-LT HCC recurrence.Methods: Data of 748 adult patients who underwent deceased donor LT for HCC between January 2015, and February 2019 were collected retrospectively from the China Liver Transplant Registry database and randomly divided into training (n = 486) and validation(n = 262) cohorts. A multivariate analysis was performed and the five-eight model was developed.Results: A total of 748 patients were included in the study; of them, 96% had hepatitis B virus (HBV) and 84% had cirrhosis. Pre-LT serum alpha-fetoprotein (AFP), tumor number and largest tumor diameter were incorporated to construct the 5-8 model which can stratify patients accurately according to their risk of recurrence into three prognostic subgroups; low-(0-5 points), medium-(6-8 points) and high-risk (> 8 points) with 2-year post-LT recurrence rate of (5,20 and 51%,p <  0.001) respectively. The 5-8 model was better than Milan, Hangzhou, and AFP-model for prediction of HCC early recurrence. These findings were confirmed by the results of the validation cohort.Conclusions: The 5-8 model is a simple validated and accurate tool for preoperative stratification of early recurrence of HCC after LT. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation is an effective therapy for end‐stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell‐mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TREML2 with acute rejection, and evaluating its prognostic value of acute rejection after liver transplantation. Methods: The study enrolled a total of 388 recipients. Among them, acute allograft rejection was observed in 54 cases. We performed single nucleotide polymorphism genotyping of CD276, including rs11072431, rs11574495, rs12593558, rs12594627, rs2127015, rs3816661 and rs7176654, and TREML2, including rs4714431, rs6915083, rs7754593, and rs9394767 from preoperative peripheral blood genome DNA. Results: We found rs2127015 of CD276, rs6915083 and rs7754593 of TREML2, and HBV infection as well were associated with acute rejection. And, rs2127015 influences CD276 expression. Moreover, we established a risk assessment model, composited by statistically proved risk factors. Conclusion: By integrating both clinical and genetic variables, liver transplant recipients can be categorized into different risk groups, and might benefit from individualized therapies. [ABSTRACT FROM AUTHOR]