Rejection In Liver Transplant Patients Research Articles

Reduced Ceramides Are Associated with Acute Rejection in Liver Transplant Patients and Skin Graft and Hepatocyte Transplant Mice, Reducing Tolerogenic Dendritic Cells.

We set up this study to understand the underlying mechanisms of reduced ceramides on immune cells in acute rejection (AR). The concentrations of ceramides and sphingomyelins were measured in the sera from hepatic transplant patients, skin graft mice and hepatocyte transplant mice by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Serum concentrations of C24 ceramide, C24:1 ceramide, C16:0 sphingomyelin, and C18:1 sphingomyelin were lower in liver transplantation (LT) recipients with than without AR. Comparisons with the results of LT patients with infection and cardiac transplant patients with cardiac allograft vasculopathy in humans and in mouse skin graft and hepatocyte transplant models suggested that the reduced C24 and C24:1 ceramides were specifically involved in AR. A ceramide synthase inhibitor, fumonisin B1 exacerbated allogeneic immune responses in vitro and in vivo, and reduced tolerogenic dendritic cells (tDCs), while increased P3-like plasmacytoid DCs (pDCs) in the draining lymph nodes from allogeneic skin graft mice. The results of mixed lymphocyte reactions with ceranib-2, an inhibitor of ceramidase, and C24 ceramide also support that increasing ceramide concentrations could benefit transplant recipients with AR. The results suggest increasing ceramides as novel therapeutic target for AR, where reduced ceramides were associated with the changes in DC subsets, in particular tDCs.

Reduced ceramides are associated with acute rejection in liver transplant patients and skin and hepatocyte transplant mice

Nayoung Kim, Hyun Ju Yoo, Yoorha Kang, Su Jung Kim, Young-In Yoon, Yeogyeong Lee, Eunyoung Tak, Jae-Joong Kim, Shin Hwang, Dong-Hwan Jung. Korean J Transplant 2022;36:116. https://doi.org/10.4285/ATW2022.F-2354

Utilization of Immunotherapy for the Treatment of Hepatocellular Carcinoma in the Peri-Transplant Setting: Transplant Oncology View.

Simple SummaryHepatocellular carcinoma is the second most common cause of cancer-related deaths and accounts for over eighty percent of primary liver cancers worldwide. Regarding the Milan Criteria, only a small portion of HCC patients are eligible for liver transplantation due to advanced-stage disease and large tumor size preventing/delaying organ allocation. Recently, the use of anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-1 and PD-L1) checkpoint inhibitors in the treatment of cancers have evolved rapidly and these therapies have been approved for the treatment of HCC, however, the main concerns about organ rejection in liver transplant patients who will be treated with ICPIs are still the same in both pre-and post-transplant setting. To alleviate those concerns, more global collaborations to explore the safety and efficacy of ICPIs in both the pre-and post-organ transplantation settings are required. The decision to administer ICPI treatment in liver transplant patients should be made on a case-by-case basis according to the goal of care and the availability and efficacy of other treatment options.Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related deaths and accounts for over eighty percent of primary liver cancers worldwide. Surgical resection and radiofrequency ablation in small tumors are included in the treatment options for HCC patients with good liver function profiles. According to the Milan Criteria, only a small portion of HCC patients are eligible for liver transplantation due to advanced-stage disease and large tumor size preventing/delaying organ allocation. Recently, the use of anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-1 and PD-L1) checkpoint inhibitors in the treatment of cancers have evolved rapidly and these therapies have been approved for the treatment of HCC. Immune checkpoint inhibitors have resulted in good clinical outcomes in pre-and post-transplant HCC patients, although, some reports showed that certain recipients may face rejection and graft loss. In this review, we aim to illustrate and summarize the utilization of immune checkpoint inhibitor therapies in pre-and post-liver transplants for HCC patients and discuss the assessment of immune checkpoint inhibitor regulators that might determine liver transplant outcomes.

Sensing Acute Cellular Rejection in Liver Transplant Patients Using Liver-Derived Extracellular Particles: A Prospective, Observational Study.

Acute cellular rejection (ACR) after liver transplantation (LT) goes along with allograft dysfunction, which is diagnosed by liver biopsy and concomitant histological analysis, representing the gold standard in clinical practice. Yet, liver biopsies are invasive, costly, time-intensive and require expert knowledge. Herein we present substantial evidence that blood plasma residing peripheral liver-derived extracellular particles (EP) could be employed to diagnose ACR non-invasively. In vitro experiments showed organ-specific EP release from primary human hepatocytes under immunological stress. Secondly, analysis of consecutive LT patients (n=11) revealed significant heightened EP concentrations days before ACR. By conducting a diagnostic accuracy study (n = 69, DRKS00011631), we explored the viability of using EP as a liquid biopsy for diagnosing ACR following LT. Consequently, novel EP populations in samples were identified using visualization of t-distributed stochastic neighbor embedding (viSNE) and self-organizing maps (FlowSOM) algorithms. As a result, the ASGR1+CD130+Annexin V+ EP subpopulation exhibited the highest accuracy for predicting ACR (area under the curve: 0.80, 95% confidence interval [CI], 0.70–0.90), with diagnostic sensitivity and specificity of 100% (95% CI, 81.67–100.0%) and 68.5% (95% CI, 55.3–79.3%), respectively. In summary, this new EP subpopulation presented the highest diagnostic accuracy for detecting ACR in LT patients.

A Neural Network Approach to Predict Acute Allograft Rejection in Liver Transplant Recipients Using Routine Laboratory Data

Background: Discovery of non-invasive methods for acute rejection in liver transplant patients would contribute to preservation of liver function in the graft. Recently, however, outcome prediction based on biostatistical models like artificial neural networks (ANNs) is increasingly becoming impressive in medicine. Objectives: The aim of this study was to obtain a predictive model based on ANN technique and to figure out the best time for early prediction of acute allograft rejection after transplantation in liver transplant recipients. Methods: Feed-forward, back-propagation neural network was developed to predict acute rejection in liver transplant recipients using clinical and biochemical data from 148 liver transplant recipients over days 3, 7, and 14 post-transplantation. Sensitivity and receiver-operating characteristic (ROC) analysis were done to reveal the importance of input variables and the performance of the neural network. Results: The results were compared with a logistic regression (LR) model using the same data. Our results showed that the data related to day 7 gave the best results in terms of ANN performance; and the most important factors in the predictive model were aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The ANN’s accuracy was 90%, sensitivity was 87%, specificity was 90% in the testing set, and the performance of the ANN was better than that of the LR model. The ANN recognized correctly eight out of ten acute rejection patients and 34 out of 36 non-rejection ones in the testing set. Conclusions: This study suggests that ANN could be a valuable adjunct to conventional liver function tests for monitoring liver transplant recipients in the early postoperative period.

Genomic Signature Predicts Acute Rejection in Liver Transplant Patients

Clinical OMICsVol. 4, No. 3 In the LabGenomic Signature Predicts Acute Rejection in Liver Transplant PatientsPublished Online:15 Jun 2017https://doi.org/10.1089/clinomi.04.03.33AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Genomic Signature Predicts Acute Rejection in Liver Transplant Patients." , 4(3), pp. 35–36FiguresReferencesRelatedDetails Volume 4Issue 3May 2017 InformationCopyright © GEN PublishingTo cite this article:Genomic Signature Predicts Acute Rejection in Liver Transplant Patients.Clinical OMICs.May 2017.35-36.http://doi.org/10.1089/clinomi.04.03.33Published in Volume: 4 Issue 3: June 15, 2017PDF download

Therapeutic Plasma Exchange for Potential Human Leukocyte Antigen Antibody-Mediated Rejection in Liver Transplant Patients

Therapeutic Plasma Exchange for Potential Human Leukocyte Antigen Antibody-Mediated Rejection in Liver Transplant Patients

Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation.

Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post-operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity.

De novo donor-specific anti-HLA antibodies mediated rejection in liver-transplant patients.

The incidence and consequences of de novo donor-specific anti-HLA antibodies (DSAs) after liver transplantation (LT) are not well known. We investigated the incidence, risk factors, and complications associated with de novo DSAs in this setting. A total of 152 de novo liver-transplant patients, without preformed anti-HLA DSAs, were tested for anti-HLA antibodies, with single-antigen bead technology, before, at transplantation, at 1, 3, 6 and 12months after transplantation, and thereafter annually and at each time they presented with increased liver-enzyme levels until the last follow-up, that is, 34 (1.5-77) months. Twenty-one patients (14%) developed de novo DSAs. Of these, five patients had C1q-binding DSAs (24%). Younger age, low exposure to calcineurin inhibitors, and noncompliance were predictive factors for de novo DSA formation. Nine of the 21 patients (43%) with de novo DSAs experienced an acute antibody-mediated rejection (AMR). Positive C4d staining was more frequently observed in liver biopsies of patients with AMR (9/9 vs. 1/12, P<0.0001). Eight patients received a B-cell targeting therapy, and one patient received polyclonal antibodies. Only one patient required retransplantation. Patient- and graft-survival rates did not differ between patients with and without DSAs. In conclusion, liver-transplant patients with liver abnormalities should be screened for DSAs and AMR.

25-Hydroxyvitamin D Levels and Acute Cellular Rejection in Liver Transplant Patients

To investigate the association between 25-hydroxyvitamin D [25(OH)D] levels prior to liver transplantation (LT) and the development of acute cellular rejection (ACR) within the first year post LT. This retrospective study included 275 consecutive LTs performed in 262 patients at Mayo Clinic in Jacksonville, Florida over 13 months. A total of 149 patients met the inclusion criteria. The correlations between 25(OH)D levels and the development, severity, and number of biopsy-proven ACR episodes were assessed. The prevalence of 25(OH)D levels <30 ng/mL was 92%. No association was found between pre LT 25(OH)D levels and the diagnosis of ACR (P = .61). Mean ± SD pre LT 25(OH)D levels were 16.1 ± 6.8 ng/mL for 48 subjects with no rejection, 16.1 ± 8.2 ng/mL for those with a mild first episode of ACR (n = 58), and 18.4 ± 12.4 ng/mL for those who experienced a moderate/severe first ACR (n = 39). However, in a subgroup analysis of patients with 25(OH)D levels <30 ng/mL, there was a statistically significant negative correlation (P = .0252) between 25(OH) D level and the ACR rate. Vitamin D insufficiency and deficiency prior to LT was prevalent in our cohort. There was no statistically significant association between low 25(OH)D levels and the diagnosis or severity of ACR or the number of rejection episodes within the first year post LT. However, there was a negative correlation between 25(OH)D levels below 30 ng/mL and the rate of ACR within 1 year post LT.

Rescue Therapy with Infliximab for Steroid Resistant Refractory Acute Rejection in Liver Transplant Patients: A Report of Two Cases

Background: Long-term survival after liver transplantation has improved gradually; however, late-onset acute rejection and chronic rejection still remain obstacles for long-term survival. Among late-phase episodes, steroid-resistant refractory rejection may be a crucial stage regarding the possibility of graft failure, and therefore an appropriate therapeutic strategy is urgently needed. We introduce the use of infliximab, which is recognized as a promising anti-rejection agent in small bowel transplantation, as a rescue therapy agent in liver transplant patients. Methods and patients: Prior to clinical use, this trial was approved by the committee overseeing the quality of medicine and ethical issues at Mie University Hospital. Patient criteria are as follows: 1. liver transplant recipients exhibiting steroid-resistant acute rejection; 2. plasma TNF-α elevated beyond the normal range (2.8 pg/ml). Between 7/2011 and 1/2012, we included 2 patients in this trial. Case 1: A 31-year-old male received ABO-incompatible living-related liver transplantation (LDLT) from his brother in May 2005 due to liver failure after a Kasai operation for biliary atresia. He had been treated with calcineurin inhibitor (CNI), mycophenolate mofetil (MMF) and steroids until the beginning of 2010, but liver transaminase levels started to increase after MMF and steroids were tapering off. A liver biopsy performed in December 2010 suggested late-onset acute rejection. MMF and steroid treatment were re-started and liver transaminase levels returned to normal. However, a second rejection episode occurred in August and subsequent steroid bolus therapy (500 mg/body, 3 days) was followed by EBV-related lymphoproliferative disease with a high EBV-DNA titer (20000 copies/ml) and symptoms of high fever and lymphadenopathy. All immunosuppressive drugs were discontinued, but a second acute rejection occurred immediately and steroid bolus therapy was now ineffective. After confirming high plasma TNF-α (12.9 pg/ml), the patient was administered 300 mg of infliximab (5 mg/kg body weight) in addition to drug conversion from CNI to MMF monotherapy in October 2011. After infliximab administration, liver transaminase levels gradually returned to normal. Following a second infliximab therapy in December 2011, the patient has been treated with MMF+steroid. Case 2: A 56-year-old male underwent LDLT from his son in June 2008 due to acute liver failure caused by primary biliary cirrhosis. He was treated with CNI+steroid, but acute rejection occurred in February 2011 probably due to reduction of CNI for renal impairment. Steroid bolus therapy was introduced and followed with CNI+MMF+steroid treatment. However, 2 episodes of acute rejection occurred in November and December of 2011 in spite of steroid bolus therapy. The highest plasma TNF-α level was 8.4 pg/ml and the patient was administered 300 mg of infliximab (5 mg/kg body weight) following diagnosis of refractory acute rejection. After infliximab therapy, liver transaminase levels decreased to around the normal range. Conclusions: The effectiveness of infliximab has been known for intestine transplantation and graft-versus-host disease after bone marrow transplantation. Although further research is essential, infliximab is a potential agent for refractory acute rejection in liver transplantation recipients.

Rescue Therapy with Infliximab for Steroid Resistant Refractory Acute Rejection in Liver Transplant Patients: A Report of Two Cases

Rescue Therapy with Infliximab for Steroid Resistant Refractory Acute Rejection in Liver Transplant Patients: A Report of Two Cases

Toll-like Receptor 3 L412F Polymorphism May Protect Against Acute Graft Rejection in Adult Patients Undergoing Liver Transplantation for Hepatitis C-Related Cirrhosis

Liver transplantation activates the innate immune system by toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. The aim of this study was to evaluate the possible association of different single nucleotide polymorphisms (SNPs) in several TLR genes with the incidence of acute graft rejection in liver transplant recipients for hepatitis C virus (HCV)-related cirrhosis. This is a single-center study of 100 adult patients who received a first whole only liver graft from deceased donors at our institution between 1988 and 2009 for cirrhosis due to HCV infection. We examined 10 SNPs in the TLR1 (S6021), TLR2 (R753Q), TLR3 (L412F), TLR4 (D299G and T399I), TLR5 (R392X), TLR6 (S249P), TLR7 (Q11L), and TLR9 (−1237T/C and −1486C/T) genes. Genotyping was carried out with the LightSNiP typing assay (TIB-MolBiol, Berlin, Germany) by analyzing the melting curves with the LightCycler 480 system (Roche Applied Science, Mannheim, Germany). Recipient́ allelic and genotypic distributions for each SNP were compared among patients with and without acute rejection within the first 3 months after transplantation. We found the homozygous mutant TT genotype for TLR3 L412F was associated with a lower rate of acute rejection when compared with the homozygous wild-type genotype [odds ratio (OR) = 0.1, 95% confidence interval (95% CI) = 0.01–0.86; P = .017], and showed a trend toward a lower graft rejection rate when compared with patients carrying one or two C alleles (OR = 0.15, 95% CI = 0.02–1.2, P = .05). No other associations with acute rejection rates were found for any other SNP evaluated. This preliminary study suggests an important role for SNP TLR3 L412F in acute rejection in liver transplant patients for HCV-related cirrhosis. Nevertheless, these findings must be prospectively validated in other cohorts of patients as well as in patients after liver transplantation for other etiologies than HCV.

Decreased Circulating CD4 +CD25 highFoxp3 + T Cells During Acute Rejection in Liver Transplant Patients

Background CD4 +CD25 highFoxP3 + regulatory T (Treg) cells have been implicated to maintain immunologic tolerance. They have been investigated in acute renal allografts rejection episodes (ARE). This study was performed to examine the frequency of peripheral blood (PB) CD4 +CD25 highFoxP3 + Treg cells among liver transplantation patients with prior benign end-stage liver diseases in relation to ARE. Methods This prospective analysis of 55 patients who underwent liver transplantation from 2004 to 2009 did not include prisoners either as donors or recipients. PB was obtained from liver transplant patients longitudinally: pretransplantation, posttransplantation within 1 year, and at the time of an episode of ARE to measure by flow cytometry circulating CD4 +CD25 highFoxP3 + T cells. Blood samples were drawn during ARE with concomitant liver biopsies. The rejector group was defined in the 14/55 cases who suffered an ARE; in the other patients with stable liver function were classified as the nonrejector group. We compared the number of circulating CD4 +CD25 highFoxP3 + T cells between the 2 groups. Results There was no difference in the levels of circulating CD4 +CD25 highFoxP3 + T cells pretransplantation. Interestingly, circulating CD4 +CD25 highFoxP3 + T cells were significantly lower among the rejector compared with the nonrejector (2.23 ± 0.54% vs 2.99 ± 0.86%; P < .01). Longitudinal analysis revealed circulating CD4 +CD25 highFoxP3 + T cells of patients in the rejector group to be significantly lower during rejection than during quiescence (2.23 ± 0.54% vs 3.68 ± 0.70%; P < .0001). The frequency of circulating CD4 +CD25 highFoxP3 + T cells negatively correlated with a Rejection Activity Index ( r = −0.80; P < .01). Conclusion Monitoring peripheral CD4 +CD25 highFoxP3 + T cell levels may be useful to evaluate the immune state, potentially acting as a sensitive marker for ARE diagnosis among liver transplantation patients. Moreover, they may contribute to the mechanisms of Treg-mediated acceptance of liver transplantations.

Use of an immune functional assay to differentiate recurrent hepatitis C from acute cellular rejection in liver transplant patients

Use of an immune functional assay to differentiate recurrent hepatitis C from acute cellular rejection in liver transplant patients

High Serum Soluble CD30 Does Not Predict Acute Rejection in Liver Transplant Patients

Increased pre- and posttransplantation values of soluble CD30 (sCD30) have been shown to be associated with acute kidney transplant rejection. We sought to study whether high sCD30 could predict rejection early after liver transplantation. The study population included 54 consecutive liver transplant patients, whose samples were collected before liver transplantation and at discharge, which was at a mean time of 3 weeks after transplantation. During the first 6 months posttransplantation, 22 patients experienced an acute rejection episode. Serum sCD30 concentrations were measured by an enzyme-linked immunoassay; changes in serum sCD30 levels posttransplantation were also expressed as relative values compared with pretransplantation results. Liver patients before transplantation displayed higher serum sCD30 values compared with healthy controls: mean values ± SD were 93 ± 58 IU/mL vs 17 ± 8 IU/mL, respectively. At 3 weeks after transplantation the mean sCD30 concentration in liver transplant patients decreased to 59 ± 42 IU/mL ( P = .005). The mean pretransplantation serum sCD30 value was slightly lower among rejecting vs nonrejecting patients: 78 ± 43 IU/mL vs 104 ± 65 IU/mL ( P = NS). Posttransplantation values in both groups decreased significantly: 47 ± 34 IU/mL in patients with rejection ( P = .014) vs 69 ± 45 IU/mL in patients without rejection ( P = .012). The relative value at 3 weeks posttransplantation decreased slightly more among patients with vs without rejection (70% vs 88%; NS). No correlation was found between serum sCD30 and anti-HLA class I antibodies or crossmatch positivity. In conclusion, neither pre- nor posttransplantation sCD30 levels were associated with acute rejection in liver transplant patients.

A case of acute humoral rejection in liver transplantation: successful treatment with plasmapheresis and mycophenolate mofetil

We present a case of a 23-year-old female who underwent orthotopic liver transplantation (OLTx) for biliary atresia, 22 years after a failed Kasai operation. Unusually, her postoperative course was complicated by severe acute humoral rejection. In this case report, we discuss her management as well as the role of plasmapheresis in treating allograft dysfunction secondary to acute humoral rejection in liver transplant patients.

Infection and rejection in liver transplant patients: a 10-year Swiss single-centre experience.

Graft rejection and infection remain major morbidities following orthotopic liver transplantation (OLT). Rejection treatment may be associated with an increased rate of infectious complications. The aim of this study was to determine the relationship between rejection, rejection therapy and the risk of associated infections. A retrospective study of all adult patients undergoing OLT between July 1987 and July 1997 at a single university medical centre was carried out. Data for all transplant recipients were collected using predetermined definitions for infectious complications. One hundred OLTs were performed on 98 patients (two patients received a second transplant). The cohort consisted of 33 women and 65 men with a mean age of 47 years. Seventy-eight patients developed a total of 228 infectious episodes: 107 bacterial, 101 viral, 17 fungal and 3 protozoan. The majority of infections occurred within the first month of OLT. Thirty patients without rejection developed 42 infectious episodes, whereas 70 patients with at least one treated rejection episode developed 186 infectious episodes. The overall rate of infection was 44.4 episodes per 1000 patient-days in the 30 days before rejection, and 94.4 episodes per 1000 patient-days in the 30 days following rejection treatment. Infections occurred more frequently during the first month post-transplantation. Following OLT, rejection is associated with a higher incidence of infection, mainly of viral origin, concurrent with increased immunosuppressive therapy.

Infection and rejection in liver transplant patients: a 10-year Swiss single-centre experience.

Graft rejection and infection remain major morbidities following orthotopic liver transplantation (OLT). Rejection treatment may be associated with an increased rate of infectious complications. The aim of this study was to determine the relationship between rejection, rejection therapy and the risk of associated infections. A retrospective study of all adult patients undergoing OLT between July 1987 and July 1997 at a single university medical centre was carried out. Data for all transplant recipients were collected using predetermined definitions for infectious complications. One hundred OLTs were performed on 98 patients (two patients received a second transplant). The cohort consisted of 33 women and 65 men with a mean age of 47 years. Seventy-eight patients developed a total of 228 infectious episodes: 107 bacterial, 101 viral, 17 fungal and 3 protozoan. The majority of infections occurred within the first month of OLT. Thirty patients without rejection developed 42 infectious episodes, whereas 70 patients with at least one treated rejection episode developed 186 infectious episodes. The overall rate of infection was 44.4 episodes per 1000 patient-days in the 30 days before rejection, and 94.4 episodes per 1000 patient-days in the 30 days following rejection treatment. Infections occurred more frequently during the first month post-transplantation. Following OLT, rejection is associated with a higher incidence of infection, mainly of viral origin, concurrent with increased immunosuppressive therapy.

Antiviral Tx May Cause Graft Rejection In Liver Transplant Patients With HCV

Antiviral Tx May Cause Graft Rejection In Liver Transplant Patients With HCV