Biomarkers of tolerance.

PURPOSE OF REVIEW: As the induction and maintenance of donor-specific tolerance is a central aim in solid organ transplantation, it is essential that clinicians are able to identify and monitor tolerance accurately and reliably. This review highlights recent advances in defining sets of biomarkers in noninvasive samples that may guide minimization and withdrawal of immunosuppression in tolerant recipients. RECENT FINDINGS: Recent studies in liver and kidney transplant recipients have identified distinct biomarker profiles that are associated with operational tolerance. Although there is some heterogeneity in the findings of these studies, these have suggested novel cellular mechanisms for the development of tolerance. SUMMARY: Multiple platforms such as microarray gene expression analysis, flow cytometry, and immune cell functional assays have been used to discover and validate composite sets of biomarkers, which identify recipients with operational tolerance both in liver and kidney transplantation. These studies suggest that distinct cellular and molecular mechanisms lead to the development of tolerance in different transplanted organs. These putative biomarker profiles now need to be validated prospectively in trials of immunosuppression withdrawal and in novel approaches to induce transplant tolerance.

Clinical relevance of human leukocyte antigen antibodies in liver, heart, lung and intestine transplantation.

PURPOSE OF REVIEW: Solid phase assays identify human leukocyte antigen (HLA) antibodies with a great sensitivity. Whether to accept or decline an organ if the virtual crossmatch is positive, when to monitor and whether to treat de-novo donor-specific antibody (DSA) posttransplant remain challenging issues for the transplant clinician. RECENT FINDINGS: Technologies that can differentiate which antibodies pose the greatest risk for antibody-mediated rejection (AMR) are evolving. Complement fixing luminex assays have been used to predict high-risk antibodies, but using these assays alone will miss some preformed antibodies. How these technologies fit into the laboratory's testing algorithm will likely need to be individualized. Posttransplant de-novo DSAs are associated with inferior outcomes. In hearts, similar to renal transplantation, acute rejection is a risk factor for developing de-novo DSA. Further data are needed to determine whether other risk factors are similar to those reported for renal transplants. Antibodies to self-antigens are increasingly recognized posttransplant and how the alloimmune response contributes to altered autoregulation is a current research focus. SUMMARY: Identification of DSA enables the clinician to make informed decisions regarding whether or not to accept an organ and if augmented immunosuppression is indicated. Monitoring for DSA posttransplant identifies recipients at a greater risk for AMR and can guide management. However, the best approach to dealing with de-novo DSA remains unclear.

Micafungin versus amphotericin B lipid complex for the prevention of invasive fungal infections in high-risk liver transplant recipients.

BACKGROUND: Limited data exist regarding echinocandins as antifungal prophylaxis in liver transplant recipients. METHODS: The efficacy and safety of targeted prophylaxis with micafungin or amphotericin B lipid complex (ABLC) was assessed in a sequential cohort of high-risk patients (posttransplantation dialysis, retransplantation, or reoperation) and compared with those without high risk who did not receive prophylaxis. Outcomes were assessed at 90 days. RESULTS: Micafungin versus ABLC recipients were older (P=0.0065) and more likely to have hepatocellular carcinoma (P=0.025). High-risks, that is, dialysis (55.6% vs. 79.2%), retransplantation (5.6% vs. 12.5%), and reoperation (38.9% vs. 20.8%) did not differ between the two groups. Invasive fungal infections developed in 11.1% (2 of 18) of micafungin recipients, 8.3% (2 of 24) of ABLC recipients, and 3% (7 of 234) of patients without high risks (P=0.12). In nondialyzed patients, ABLC versus micafungin recipients had significantly higher serum creatinine on day 14 (P=0.04). However, renal and hepatic function, rejection, graft loss, and mortality did not differ for the two groups on day 90. CONCLUSIONS: Targeted prophylaxis with micafungin or ABLC decreased the risk of mycoses in high-risk recipients compared with that in low-risk recipients. Compared with ABLC, however, micafungin appeared to be associated with lower early-renal dysfunction and no additional risk of hepatic dysfunction.

Immunogenicity of decellularized porcine liver for bioengineered hepatic tissue.

Liver disease affects millions of patients each year. The field of regenerative medicine promises alternative therapeutic approaches, including the potential to bioengineer replacement hepatic tissue. One approach combines cells with acellular scaffolds derived from animal tissue. The goal of this study was to scale up our rodent liver decellularization method to livers of a clinically relevant size. Porcine livers were cannulated via the hepatic artery, then perfused with PBS, followed by successive Triton X-100 and SDS solutions in saline buffer. After several days of rinsing, decellularized liver samples were histologically analyzed. In addition, biopsy specimens of decellularized scaffolds were seeded with hepatoblastoma cells for cytotoxicity testing or implanted s.c. into rodents to investigate scaffold immunogenicity. Histological staining confirmed cellular clearance from pig livers, with removal of nuclei and cytoskeletal components and widespread preservation of structural extracellular molecules. Scanning electron microscopy confirmed preservation of an intact liver capsule, a porous acellular lattice structure with intact vessels and striated basement membrane. Liver scaffolds supported cells over 21 days, and no increased immune response was seen with either allogeneic (rat-into-rat) or xenogeneic (pig-into-rat) transplants over 28 days, compared with sham-operated on controls. These studies demonstrate that successful decellularization of the porcine liver could be achieved with protocols developed for rat livers, yielding nonimmunogenic scaffolds for future hepatic bioengineering studies.

Tacrolimus dose individualization in "de novo" patients after 10 years of experience in liver transplantation: pharmacokinetic considerations and patient pathophysiology.

AIM: To determine how changes in tacrolimus (TAC) immunosuppression clinical practice, in the first 15 days post liver transplantation (LT) and across a decade, impact a clinical covariate - pharmacokinetic (PK) model, developed in data from 1998, thus testing its utility in dose individualization across time. Patient cohorts from 1998 (Reference: R-1998) and 2007 (EVALUATION: E-2007) were compared. METHODS: Analysis of monitoring observations (Cmin and Cmin/dose) and the biochemical variables aspartate aminotransferase (AST), hematocrit (HCT), albumin (ALB) and serum creatinine (SCr) was done for 0 - 3 and 4 - 15 days post transplantation (PT). The population PK model developed for R-1998 [1] was re-evaluated for the two cohorts. RESULTS: Significant differences in R-1998 vs. E-2007 existed in Cmin and Cmin/dose and in covariates AST (as hepatic function marker) and SCr (as toxicity marker). E-2007 had lower levels of Cmin and Cmin/dose (1/CL), lower AST with faster recovery and lower variability in Cmin/dose for similar dose. AST was a covariate on CL/F in the 0 - 3 day PT period. In 4 - 15 days PT for E-2007, low levels of HCT and ALB as CL/F predictors confirmed a subgroup with higher CL/F (23.8 l/h vs. 19.3 l/h). The R-1998 model's original structure was confirmed. CONCLUSIONS: Ten years of use of TAC shows gain in therapeutic targeting efficiency, due to improvement in LT methods, knowledge of the drug and consideration of PK steady state. The remaining uncertainty with TAC monitoring in LT can be resolved with application of PK principles combined with patients' diosyncrasies in the model developed for TAC dose individualization in R-1998. The applicability of the model as nucleus in Bayes individualization remains intact across a decade.

De novo donor-specific HLA antibodies decrease patient and graft survival in liver transplant recipients.

The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre- and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.

Human hepatic stellate cells inhibit T-cell response through B7-H1 pathway.

BACKGROUND: The liver is an immunologic privileged organ; liver allografts are accepted across major histocompatibility complex barriers in many species. However, hepatocyte transplants are acutely rejected, suggesting a role for liver nonparenchymal cells in regulating the immunoresponse. We have shown potent immunoregulatory activity of hepatic stellate cells (HSCs) in mice. The aim of this study was to examine the immunoregulatory activity of human HSCs. METHODS: HSCs were isolated from normal human livers for analyses of their impact on T-cell response. RESULTS: HSCs expressed low HLA-DR and costimulatory molecules CD40 and CD80 but constitutively expressed high levels of CD54. Interferon-γ stimulated HSCs to express B7-H1 in a dose-dependent manner and produce the suppressive cytokines interleukin-6, interleukin-10, and transforming growth factor-ß but did not affect expression of HLA-DR, CD40, and CD80. Human HSCs did not stimulate allogeneic T-cell proliferative response, indicating that they are not professional antigen-presenting cells. HSCs markedly inhibited T-cell response elicited by either allogeneic antigen-presenting cells or CD3/CD28 beads, which was associated with increases in activated CD4 and CD8 T-cell apoptosis. Addition of anti-B7-H1 blocking antibody significantly reversed the inhibitory effect. CONCLUSIONS: Human HSCs demonstrate potent immunoregulatory activity via B7-H1-mediated induction of apoptosis in activated T cells. Understanding of the involved mechanisms may lead to development of novel therapeutic approaches for treatment of liver diseases.

Impact of donor-specific antibodies on results of liver transplantation.

PURPOSE OF REVIEW: To critically examine the recent literature evaluating the importance of HLA donor-specific antibody (DSA) impact on liver transplant and simultaneous liver-kidney transplant (SLKT) outcomes. RECENT FINDINGS: Many preformed DSAs, especially of low mean fluorescence intensity (MFI), are absorbed by the liver at transplant. However, patients with post-liver transplant DSA, especially of higher MFI, are at increased risk of acute and chronic rejection. C4d staining, when positive, may be helpful but lacks sensitivity especially in formalin tissue. SLKT recipients may need close follow-up when class II DSA is found, as the liver protects the kidney from hyperacute rejection, but can still cause early renal antibody-mediated rejection, liver allograft rejection, and impair patient, liver allograft, and renal allograft survival. SUMMARY: Some DSAs are relevant in liver transplant and can lead to acute and chronic allograft rejection. However, before clinical practice patterns can change we must create unified diagnostic criteria, define the pathologic potential of different DSAs, and improve the specificity of current testing.

ABO-incompatible liver transplantation in acute liver failure: a single Portuguese center study.

INTRODUCTION: ABO-incompatible liver transplantation (ABOi LT) is considered to be a rescue option in emergency transplantation. Herein, we have reported our experience with ABOi LT including long-term survival and major complications in these situations. PATIENT AND METHODS: ABOi LT was performed in cases of severe hepatic failure with imminent death. The standard immunosuppression consisted of basiliximab, corticosteroids, tacrolimus, and mycophenolate mofetil. Pretransplantation patients with anti-ABO titers above 16 underwent plasmapheresis. If the titer was above 128, intravenous immunoglobulin (IVIG) was added at the end of plasmapheresis. The therapeutic approach was based on the clinical situation, hepatic function, and titer evolution. A rapid increase in titer required five consecutive plasmapheresis sessions followed by administration of IVIG, and at the end of the fifth session, rituximab. RESULTS: From January 2009 to July 2012, 10 patients, including 4 men and 6 women of mean age 47.8 years (range, 29 to 64 years), underwent ABOi LT. At a mean follow-up of 19.6 months (range, 2 days to 39 months), 5 patients are alive including 4 with their original grafts. One patient was retransplanted at 9 months. Major complications were infections, which were responsible for 3 deaths due to multiorgan septic failure (2 during the first month); rejection episodes (4 biopsy-proven of humoral rejections in 3 patients and 1 cellular rejection) and biliary. CONCLUSION: The use of ABOi LT as a life-saving procedure is justifiable in emergencies when no other donor is available. With careful recipient selection close monitoring of hemagglutinins and specific immunosuppression we have obtained acceptable outcomes.

Elevation of CD4+ differentiated memory T cells is associated with acute cellular and antibody-mediated rejection after liver transplantation.

BACKGROUND: It is now well known that the outcome after allogeneic transplantation, such as incidence of acute rejections, very much depends on the individual's immune reactivity status. There is also increasing evidence that the presence of preexisting memory T cells can affect antigraft immune responses. METHODS: In a prospective study, we monitored peripheral CD4 and CD8 central memory, effector memory, and terminal differentiated effector memory (TEMRA) T cells in 55 patients who underwent deceased liver transplantation and received conventional immunosuppressive treatment with or without basiliximab induction. The primary endpoint of the study was acute allograft rejection during a 1-year follow-up period. RESULTS: We observed significantly increased proportions of CD4 and CD8 TEMRA cells in patients before transplantation compared with healthy controls (P=0.006 and 0.009, respectively). This characteristic was independent of the underlying disease. In patients with no signs of acute rejection, we observed an immediate reduction of CD4 TEMRA cells. In contrast, patients who experienced acute cellular rejection, and especially antibody-mediated rejection, displayed persistent elevated TEMRA cells (P=0.017 and 0.027, respectively). Basiliximab induction therapy did not influence CD4 and CD8 TEMRA numbers. CONCLUSIONS: Conventional immunosuppressive or basiliximab treatment cannot control the persistence of TEMRA T cells, which may contribute to acute cellular rejection and antibody-mediated rejection after liver transplantation. In the future, specific targeting of TEMRA cells in selected patients may prevent the occurrence of difficult to treat steroid-resistant rejections, thereby leading to improved patient outcome.

Significance of true-positive and false-positive pretransplantation lymphocytotoxic crossmatch in primary liver allograft outcomes.

BACKGROUND: At the time of transplantation, a recipient's serum is tested against the prospective donor's lymphocytes to identify specific reactivity and to look for a donor-specific crossmatch (CXM). Here, we investigated the relationship between the pretransplantation lymphocytotoxic CXM results and the long-term outcome of liver transplantation at a single center. METHODS: From October 1998 to April 2011, medical records, laboratory data, and pretransplantation lymphocytotoxic CXM results were collected from 1133 consecutive liver transplant recipients. RESULTS: We performed liver transplantations on 80 (7.1%) patients after a true-positive CXM (t+CXM). The t+CXM group exhibited higher initial aminotransferase levels immediately after transplantation compared with a negative CXM group. However, no significant differences in rejection, biliary or vascular complications, viral disease recurrence, or de novo malignancies were found. Although overall graft and patient survival did not differ between the groups, liver-specific graft survival was inferior in the t+CXM group. It was also found that, in 42 (3.7%) recipients, initially positive results converted to final negative results after the elimination of immunoglobulin M autoantibodies. We defined this subpopulation as a false-positive CXM. Significantly decreased posttransplantation aminotransferase levels with a higher incidence of de novo malignancies were observed in this group compared with negative controls. CONCLUSION: Our findings demonstrate that t+CXM transplants show increased aspartate aminotransferase and alanine aminotransferase peak immediately after transplantation, which influences liver-specific graft outcomes. Additionally, the presence of circulating immunoglobulin M autoantibodies against recipients' own antigens may be protective in liver grafts. However, this may be a predisposing factor for de novo malignancies.

Acute cellular rejection is associated with matrix metalloproteinase-2 genotype chimerism after orthotopic liver transplantation.

PURPOSE: Chimerism in transplantation medicine refers to the coexistence of cells of donor and recipient origin. Their existence in relation to possible pathological mechanisms remains largely unknown. We used donor-recipient mismatches for matrix metalloproteinases (MMP) gene polymorphisms in liver biopsies and in blood as a marker for chimerism after orthotopic liver transplantation (OLT). The second aim of this study was to evaluate these polymorphisms in relation to clinical outcome such as ischemia-reperfusion injury (IRI) and acute cellular rejection (ACR). METHODS: MMP-2 and MMP-9 promoter polymorphism donor-recipient mismatches were determined in 147 OLT patients. The relationship between these MMP polymorphism mismatches in donor and recipient DNA with the development of IRI and ACR after OLT was evaluated. Liver biopsy specimens and peripheral blood samples were subsequently evaluated for the presence of chimerism, also in relation to these complications. RESULTS: MMP polymorphism donor-recipient mismatches were found in 53.7% (MMP-2) and 35.5% (MMP-9) of the OLT patients but no relation was observed with IRI or ACR. Chimerism in liver biopsy specimens was found to be present in 28.8% (MMP-2) and 16.2% (MMP-9) of the cases. Liver chimerism in MMP-2 was found to be significantly associated with ACR after OLT (χ(2) 6.4, P = .01). Multivariate analysis revealed MMP-2 chimerism to be an independent risk factor for ACR after OLT even adjusted for Model for End-stage Liver Disease score (hazard ratio = 3.83, P = .03). In addition, evidence of donor chimerism was found in peripheral blood samples of the recipients in some cases. CONCLUSION: Chimerism after OLT can be found in liver biopsy specimens and in peripheral blood. MMP donor-recipient polymorphism mismatches are good markers for assessing chimerism after OLT. In the multivariate analysis, liver chimerism in MMP-2 was found to be significantly associated with the development of ACR after OLT.

Living-related liver transplantation in Diego blood group disparity: a case report.

To date, only limited cases of Diego blood group disparity in liver transplantation have been reported, and no cases with a long-term clinical course have been documented. Herein, we report a case of Diego blood group disparity in liver transplantation with details of long-term follow-up. The recipient was a 47-year-old woman with primary biliary cirrhosis; her 18-year-old daughter was the donor. Both recipient and donor were of blood type O according to the ABO blood group system. Preoperative serological tests showed the presence of antibodies against the Di(a) antigen only in the recipient, and not in the donor. Thus, the Diego phenotype was Di(a+) in the donor and Di(a-) in the recipient. Living-related liver transplantation was performed in July 2009. Immediate graft function was obtained, and no signs of humoral or cellular rejection were observed during the postoperative period. Further, anti-Di(a) antibodies were not detected throughout the postoperative course. The patient is alive and shows no signs of humoral rejection 34 months after liver transplantation. Liver transplantation has been performed successfully in cases of Diego blood group disparity.

Hepatitis E virus infection in a liver transplant recipient in the United States: a case report.

BACKGROUND: Chronic infection with hepatitis E virus (HEV) has recently been recognized in immunocompromised or immunosuppressed individuals. CASE REPORT: We report a case of concurrent HEV and human herpes virus-6 (HHV-6) infection, documented by serum HEV RNA and HHV-6 DNA, in an orthotopic liver transplant (OLT) recipient in the United States, where HEV genotype 3 infection, although prevalent, is considered to be self-limited and almost always asymptomatic. The coinfection was accompanied by elevated serum aminotransaminases, liver biopsies demonstrating chronic hepatitis, and the presence of HEV RNA in the tissue. After lowering of immunosuppressive therapy and 2 courses of valganciclovir, sequential clearance of the viruses and normalization of the serum aminotransaminases were observed. CONCLUSIONS: HEV infection can lead to chronic hepatitis in OLT recipients, and evaluation of this virus should be considered in immunosuppressed individuals with unexplained liver test abnormalities.

Immunoglobulin G4-associated de novo autoimmune hepatitis after liver transplantation for chronic hepatitis B- and C-related cirrhosis and hepatocellular carcinoma: a case report with literature review.

Immunoglobulin G4 (IgG4)-associated autoimmune hepatitis (AIH) was recognized as a new disease entity; however, IgG4-associated de novo AIH after the liver transplantation had not been reported yet. Herein we have described a 56-year-old man who developed IgG4 de novo AIH as 1 year-post liver transplantation after receiving pegylated interferon alpha-2a and ribavirin therapy for hepatitis C virus recurrence. The histopathologic evidence showed an aggressive lymphoplasmacytic interface hepatitis with centrilobular necrosis (plasma cells > 30%) and IgG4-positive plasma cells (>10 per high power field). Serum IgG (9220 mg/dL) and IgG4 (3289 mg/dL) were also elevated. Improvement of liver function tests (LFTs) by prednisone and azathioprine therapy are manifested as normalized alanine aminotransferase and IgG levels. IgG4 relates to more severe histological activity; however, it is believed to be a good prognostic predictor of a response to prednisone plus azathioprine therapy especially with early diagnosis and timely management.

KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury.

BACKGROUND: Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial. METHODS: KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups. RESULTS: KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P<0.05), with KIR2DL3 and KIR2DS1 exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4 significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3 recipients and donors having C1 ligands (log rank, P<0.019 at 1 year; hazards ratio [HR], 0.321; 95% confidence interval [CI], 0.107-0.962; P=0.042), whereas KIR2DS1 and KIR2DS4 recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156-27.369; P=0.002 for KIR2DS1; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267-11.365; P=0.017 for KIR2DS4). CONCLUSIONS: This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4/C ligands also influence short-term graft survival.

Use of rifabutin for the treatment of a latent tuberculosis infection in a patient after solid organ transplantation.

Latent tuberculosis infection is an important problem for solid organ transplant recipients because of the frequency of its occurrence and its potential for reactivation. Because of the high mortality rate associated with active tuberculosis infections in transplant recipients, guidelines from the American Thoracic Society recommend treatment for latent tuberculosis in this population. However, the choice of treatments is often difficult because liver transplant recipients may be more sensitive to isoniazid hepatotoxicity, and rifampin has significant drug interactions with the calcineurin inhibitors used for immunosuppression. Two prior case reports described success with the use of rifabutin, a rifampin alternative, as part of a multidrug treatment regimen for active tuberculosis in posttransplant patients; however, there is no prior literature describing any experience with rifabutin for the treatment of latent tuberculosis in the posttransplant setting. We present a summary of tacrolimus drug levels and corresponding dose requirements for a single posttransplant patient during the administration of 3 different latent tuberculosis drug regimens: rifampin alone, rifampin plus ketoconazole, and rifabutin. In this patient's case, rifabutin allowed the maintenance of adequate tacrolimus levels, although an approximate 2.5-fold increase in the dose was required. Rifampin alone was associated with inadequate immunosuppressant levels, and rifampin plus ketoconazole was associated with a problematically prolonged QT interval and concerns about inadequate tuberculosis treatment.

Distinct microRNA profiles are associated with the severity of hepatitis C virus recurrence and acute cellular rejection after liver transplantation.

Recurrent hepatitis C virus (HCV) infection is associated with accelerated fibrosis rates after liver transplantation (LT) and is the leading cause of graft failure. Furthermore, distinguishing recurrent HCV from acute cellular rejection (ACR) can be problematic, and this can lead to inappropriate treatments and adverse outcomes. We hypothesized that intragraft microRNA (miRNA) expression profiles could distinguish the severity of recurrent HCV and differentiate recurrent HCV from ACR. We established meticulously matched post-LT patient cohorts in order to derive robust global miRNA expression profiles and minimize the impact of variables known to influence HCV recurrence. These cohorts consisted of patients with slow HCV fibrosis progression (Ishak stage < F2), fast HCV fibrosis progression (Ishak stage ≥ F2), ACR, and nonviral etiologies. We found increased intragraft expression of miRNA-146a, miRNA-19a, miRNA-20a, and miRNA-let7e in slow progressors versus fast progressors, and we validated these findings with quantitative PCR. This miRNA network regulates the expression of cardinal genes implicated in promoting antifibrogenic, antiangiogenic, and anti-inflammatory pathways. miRNA-19a and miRNA-20a were also specifically detected in the serum of slow progressors. Furthermore, intragraft miRNA expression distinguished fast HCV progression from ACR. Here, changes in the expression of key miRNAs regulating fibrogenic and angiogenic pathways were associated with fast HCV progression. We demonstrate specific miRNA expression signatures that discriminate the rates of fibrosis progression in patients with recurrent HCV, and we distinguish recurrent HCV from ACR after LT. A pathway analysis indicates that specific miRNAs may play a regulatory role in these processes. Selected miRNAs may serve as intragraft and serum biomarkers for recurrent HCV after LT and help to distinguish between ACR and recurrent HCV.

Recipient cytotoxic T lymphocyte antigen 4 +49 single-nucleotide polymorphism is not associated with acute rejection after liver transplantation in Chinese population.

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) in Cytotoxic T lymphocyte antigen 4 (CTLA-4) gene have been detected and proved to associate with the incidence of rejection after transplantation. However, previous studies gained inconsistent results about the association between CTLA-4 +49 single-nucleotide polymorphism and susceptibility of allograft rejection. Therefore we sought to clarify whether CTLA-4 +49 SNP influences the incidence of acute rejection after liver transplantation in Chinese population. METHODS: Genomic DNA from 335 liver transplant recipients was genotyped for CTLA-4 +49 SNP by DNA sequencing. Acute rejection was confirmed by pathologic evidences. The association between CTLA-4 +49 SNP and incidence of acute rejection was then analyzed by dominant, recessive, codominant and overdominant models. RESULTS: The incidence of acute rejection within the first 3 months was 11.9%. In acute rejectors, the frequency was 45% for G/G, 10% for A/A and 45% for A/G respectively, compared with 47.5% for G/G, 10.8% for A/A and 41.7% for A/G in non-acute rejectors. And no significant difference of allele distribution between these 2 groups was detected. CONCLUSIONS: This study suggests that CTLA-4 +49 SNP is not associated with acute rejection after liver transplantation in Chinese population.