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The prognosis of patients after liver transplantation (LTx) with high Model of End-Stage Liver Disease (MELD) score (30) is predicted, but patients with lower MELD scores (30) have no conclusive studies of pre- and post-transplant risk factors that influence the long-term outcome.This retrospective study reviewed 268 recipients with MELD score 30, from 2008 to 2013 in our institution, for evaluation of pre-transplant risk factors including patients' clinical background data, pre-transplant lymphocyte subpopulation, and early post-transplant infection complication as predictors for long-term survival after LTx.The post-transplant patients' survival estimates were 90.7%, 85.1%, and 83.6% at 1, 3, and 5 years, respectively. In multivariate analysis, age55years, presence of ascites, cluster of differentiation (CD)3 93.2 (count/μL), CD4/CD8 2.4, fungal infection, and more than one site of fungal colonization significantly influenced survival (P = .0003, P = .002, P = .04, P = .004, P .0001, and P.0001, respectively). We also noticed that these five factors accumulatively influence the long-term survival rate; this means that in the presence of any two risk factors, the 5-year survival can still be 88.4%, whereas in the presence of any three risk factors, the survival rate dropped to only 57.1%.Older patients in the presence of pre-transplant low immune cell number and ascites in association with post-transplant fungal infection are the independent risk factors in MELD scores 30 LTx groups for long-term survival. Patients in these groups with any of the three factors had inferior long-term survival results.

Myeloid-derived suppressor cells (MDSCs) play an important role in the regulation of the immune response. MDSC expansion occurs in many circumstances, including cancer, inflammation, stresses, and transplant tolerance. Liver transplants in mice are spontaneously accepted, but hepatocyte transplants are acutely rejected, suggesting the immunoregulatory activities of liver nonparenchymal cells. We have reported that hepatic stellate cells (HpSCs), the stromal cells in the liver, are immensely immunosuppressive and can effectively protect islet transplants via induction of MDSCs. The present study shows that the addition of HpSCs into dendritic cell (DC) culture promoted development of MDSCs, instead of DCs, which was highly dependent on complement component 3 (C3) from HpSCs. The C3(-/-) HpSCs lost their ability to induce MDSCs and, consequently, failed to protect the cotransplanted islet allografts. HpSCs produced complement activation factor B and factor D which then enhanced C3 cleavage to activation products iC3b and C3d. Addition of exogenous iC3b, but not C3d, into the DC culture led to the differentiation of MDSCs with potent immune-inhibitory function. These findings provide novel mechanistic insights into the differentiation of myeloid cells mediated by local tissue cells, and may assist in the development of MDSC-based therapy in clinical settings.

Background Side effects of lifetime immunosuppression for cell transplants often outweigh the benefits; therefore, induction of transplant tolerance is needed. We have shown that cotransplantation with myeloid-derived suppressor cells (MDSC) effectively protect islet allografts from rejection without requirement of immunosuppression. This study was to investigate the underlying mechanisms. Methods MDSC were generated by addition of hepatic stellate cells from various stain mice into dendritic cell (DC) culture. The quality of MDSC was monitored by phenotype and function analyses. MDSC mixed with islet allografts were transplanted into diabetic recipients. T-cell response was analyzed after transplantation by using flow and histochemical analyses, and was compared with islet alone and islet/DC transplant groups. B7-H1 knockout mice were used to determine the role of B7-H1 on MDSC in regulation of T-cell response. Results Cotransplantation with MDSC (not DC) effectively protected islet allografts without requirement of immunosuppression. This is associated with attenuation of CD8 T cells in the grafts and marked expansion of regulatory T (Treg) cells, which contributed to MDSC-induced T-cell hyporesponsiveness. Antigen-specific Treg cells were prone to accumulate in lymphoid organs close to the grafts. Both in vitro and in vivo data demonstrated that B7-H1 was absolutely required for MDSC to exert immune regulatory activity and induction of Treg cells. Conclusion The described approach holds great clinical application potential and may overcome the limitation of requiring chronic administration of immunosuppression in cell transplants. Understanding the underlying mechanisms will facilitate the development of this novel therapeutic strategy.

Aim: To assess the efficacy and tolerability of early combination therapy with rosiglitazone (RSG) and glimepiride (GLIM) vs. GLIM monotherapy in patients with type 2 diabetes mellitus (T2DM). Methods: Strategies for the addition of RSG in combination with GLIM were evaluated with data from two randomized, double-blind, placebo (PBO)-controlled studies. Study A – addition of RSG (4 or 8 mg) or PBO to continued GLIM 3 mg once daily; study B – addition of low-dose RSG (4 mg) prior to uptitration of GLIM (from 2 to 4 mg) vs. continued uptitration of GLIM (from 2 to 8 mg). Results: Study A reported significant reductions in fasting plasma glucose (FPG) from baseline to week 26 with the addition of both 4 and 8 mg RSG to GLIM 3 mg [−21 mg/dl (−1.2 mmol/l), p = 0.0019 and −43 mg/dl (−2.4 mmol/l), p

Aim: This study assessed the efficacy and safety of rosiglitazone and metformin (RSG/MET) fixed-dose combination (AVANDAMET) as initial therapy in patients with uncontrolled type 2 diabetes compared with monotherapy with either RSG or MET after 32 weeks of treatment. Methods: A total of 468 drug-naive patients with uncontrolled type 2 diabetes were recruited for this multicentre, double-blind trial if their glycated haemoglobin (A1c) was greater than 7.5%, but less than or equal to 11%, and their fasting plasma glucose (FPG) was less than or equal to 15 mmol/l. Patients were randomized to 32 weeks of blinded treatment with either RSG/MET fixed-dose combination (n = 155), MET (n = 154) or RSG (n = 159). The groups were comparable at baseline, with mean A1c of 8.8% and FPG of 11 mmol/l. RSG/MET was initiated with a total daily dose of 2 mg/500 mg and could be increased up to 8 mg/2000 mg; MET therapy began with a total daily dose of 500 mg and could be increased up to 2000 mg; and RSG treatment began with a total daily dose of 4 mg and could be increased up to 8 mg. Medication was uptitrated during on-therapy visits based on failure to attain glycaemic target of mean daily glucose less than or equal to 6.1 mmol/l (unless at maximum tolerated dose). Patients were assessed for efficacy and safety at nine visits over a 32-week treatment period. This was a trial designed to show greater efficacy of RSG/MET combination therapy compared with MET or RSG monotherapy. The primary end point was change in A1c from baseline to week 32. Secondary end points included the proportion of patients achieving recommended A1c and FPG targets for glycaemic control and change from baseline in FPG, free fatty acid, lipids, insulin, insulin sensitivity, C-reactive protein and adiponectin. Safety evaluations included adverse-event (AE) monitoring, changes in weight and clinical laboratory evaluations. Results: At week 32, RSG/MET showed significant improvements in A1c from a baseline of 8.9 ± 1.1% to 6.6 ± 1.0% at study end, and this 2.3% reduction was significantly greater than the reductions achieved individually with MET (−1.8%; p = 0.0008) and RSG (−1.6%; p < 0.0001). The greatest mean decrease in FPG was seen with RSG/MET (−4.1 mmol/l) and was significant compared with MET (−2.8 mmol/l; p < 0.0001) and RSG (−2.6 mmol/l; p < 0.0001). Target A1c of less than or equal to 6.5% and less than 7% were achieved in more patients in the RSG/MET group (60% and 77%) than with MET (39% and 57%) or RSG (35% and 58%) respectively. Treatment was well tolerated, with nausea, vomiting and diarrhoea as the most commonly reported AEs. Oedema was comparable between RSG/MET (6%) and RSG (7%) and lower in the MET group (3%). No new safety and tolerability issues were observed in the RSG/MET group. Conclusions: As first-line therapy in patients with uncontrolled type 2 diabetes, RSG/MET fixed-dose combination therapy achieved significant reductions in A1c and FPG compared with either RSG or MET monotherapy. RSG/MET was generally well tolerated as initial therapy, with no new tolerability issues identified with the fixed-dose combination.

Introduction Acute humoral rejection (AHR), a rare complication in orthotopic liver transplantation (OLT), responds poorly to conventional therapies. Bortezomib, a proteasome inhibitor, has been shown to be effective in treating plasma cell–derived tumors and acute rejection episodes after renal transplantation. Herein, we have reported our clinical experience with bortezomib as a novel approach to treat AHR after OLT. Methods We retrospectively analyzed the 247 adult OLTs performed from January 2007 to April 2011. Patients with AHR who were treated with steroid pulses, rituximab (375 mg/m2), and plasmapheresis (PP) were assigned to group A. Group B subjects were prescribed steroid pulses, rituximab, PP, and bortezomib (1.3 mg/m2), after March 2009. Results Among the 9 patients (3.6%) diagnosed with AHR, all subjects in group A (n = 3) died within several days after AHR, whereas 4/6 (66.7%) group B patients were rescued and 3 (50%) survived at a mean follow-up 22.3 months (range, 18–26). Conclusion Proteasome inhibitor-based therapies provide a more effective strategy to treat AHR after OLT.

Hepatitis C recurrence after liver transplantation is universal and is a major cause of long-term graft failure. Improving the effectiveness of recurrent hepatitis C treatment is extremely important. We studied 35 anti-hepatitis C virus (HCV)-positive patients who underwent liver transplantation. Among the 35 patients, 25 patients had recurrent hepatitis C and received antiviral treatment. HCV RNA load after liver transplantation was increased by 3.68-fold. The antiviral treatment regimen comprised pegylated-interferon (180 μg) every 2 weeks and ribavirin at a dose of 200-400 mg every day. The treatment duration was flexible and individualized, and depended on viral response to treatment. The dosage of tacrolimus was decreased gradually to minimize immunocompromise. Median (interquartile) serum level of tacrolimus was 6.9 (6-8.9) ng/mL at initiation of treatment and 3.8 (3.6-5) ng/mL at the end of treatment. One patient (4.0%) was withdrawn from the study, and three patients (12%) died of infection during treatment. At end of treatment, 18 of 25 patients (72%) were negative for serum HCV RNA. After an additional 6 months following the end of treatment, 16 of the 25 patients (64%) had sustained viral response (SVR) and only two patients had HCV relapse. The 1-year, 3-year and 5-year survival rates were 91.4%, 84.5% and 84.5% for all patients and 88.0%, 82.8% and 82.8% for the 25 patients who received antiviral therapy. In conclusion, recurrent HCV infection is an important issue in liver transplantation. The flexible regimen of antiviral therapy and individualized immunosuppressive agents that was applied in this study achieved a SVR rate of 64%.

Background/Aims The liver lies downstream of the gut, and is constantly exposed to bacteria. Liver dendritic cells (DC) are known to possess properties of tolerance, and respond to LPS differently when compared to conventional DC, but the underlying mechanisms are not completely understood. The aim of this study was to evaluate liver DC response to LPS stimulation. Methods Liver or spleen derived DC were isoloated from mice treated with plasmid-GM-CSF hydrodynamic injection. The surface molecules and TLR4 expression on DC and cytokine productions of LPS stimulated DC were determinded by FACS analysis, ELISA and qPCR. The ability of DC to elicit T cell responses and differentiation were examined by MLR/CTL assay and qPCR for molecular markers related to Th1/Th2/Treg. Results In this study, we demonstrated that the threshold of LPS stimulation for liver DC was markedly higher than spleen DC, even though the expression of TLR4 on both DCs was comparable. In contrast to spleen DC that produced high levels of IL-12 and induced Th1 response upon LPS stimulation, LPS-liver DC preferentially produced IL-10 and IL-27, instead of IL-12. In addition, liver DC induced T cell hyporesponsiveness, associated with selective expansion of CD4 + Foxp3 + T regulatory cells. Addition of exogenous IL-12 only slightly enhanced liver DC-induced T cell response. Interestingly, abrogation of IL-27 ligation by using IL-27R −/− T cells synergistically augmented the effect of IL-12, suggesting that IL-27 produced by liver DC plays a crucial role in induction of T cell hyporesponsiveness. Conclusions Liver DC respond distinctly to LPS stimulation by secreting IL-27 which synergizes with silencing of bioactive IL-12 activity leading to profound T cell inhibition.