Rejection In Liver Transplantation Research Articles

Profiling the pattern of human TRB/IGH-CDR3 repertoire in liver transplantation patients via high-throughput sequencing analysis.

Immune processes in liver transplantation remain poorly understood. Acute allograft rejection in liver transplantation is a kind of T cell-mediated inflammatory disease accompaniedby inflammatory cell infiltration. However, the effect of acute allograft rejection on the immunological characteristics of TCRs in peripheralbloodmononuclearcell is unknown. In this study, we characterized the pattern of the human T cell receptor beta chain (TRB) and immunoglobulin heavy chain (IGH) complementarity-determining region 3 (CDR3) repertoires via high-throughput sequencing in 11 acute allograft rejection (AG) cases, 23 patients with stable allograft liver function (ST) who had liver transplantation performed and 20 healthy controls (HC). The diversity of TRB-CDR3 was significantly reduced in the AG group compared with the ST group and healthy controls (HC). The CDR3 and N-addition length distribution were not significantly different between the AG and ST groups. However, N-addition length distribution was significantly changed compared to HC. It seemed that AG used more short N-additions and healthy people used more long N-additions in TRB-CDR3 repertoire. Our findings suggested that the TRB-CDR3 region of AG had distinctive V gene use compared with that of HC. The characteristics of ST seemed to be in between those of AG and HC although the difference is not significant. Cluster analysis showed that the TRB repertoire could not effectively distinguish AG from ST. This research might give to a better understanding of the immune process of liver transplantation.

Role of Budesonide for the Treatment of Rejection in Pediatric Liver Transplantation.

Corticosteroids are an integral part of liver transplant (LT) immunosuppression regimens but are often accompanied by many adverse effects. Budesonide is an oral corticosteroid with extensive (80%-90%) hepatic first-pass metabolism and minimal systemic absorption. The aim of this study was to examine the safety and efficacy of budesonide for management of acute cellular rejection (ACR) in pediatric LT recipients. A retrospective descriptive analysis was performed for all pediatric patients who underwent LT at our center and were prescribed oral budesonide for the treatment of ACR. Alanine aminotransferase (ALT) values and documented adverse effects were reviewed. Twenty-nine patients were prescribed budesonide for the treatment of ACR; 65.5% with biopsy-proven acute rejection and 34.5% with presumed ACR. There was a significant decrease in ALT noted from the time of rejection when compared to values 1 month (P = 0.0011), 3 months (P = 0.0003), and 6 months (P = 0.0001) after treatment with budesonide. There was no difference noted between patient baseline ALT levels before rejection when compared to 1, 3, and 6 months posttreatment values suggesting resolution of rejection. Three patients required conversion from budesonide to systemic steroids. There were no discontinuations of budesonide secondary to adverse effects. Oral budesonide may be a promising alternative to systemic corticosteroids for the management of mild/moderate ACR and for empiric treatment of ACR in select pediatric LT recipients. Data from this study may provide the foundation for larger, prospective, multicenter trials to assess the effectiveness of budesonide in the treatment of ACR.

Beyond 10years, with or without an intestinal graft: Present and future?

Long-term outcomes in children undergoing intestinal transplantation remain unclear. Seventy-one children underwent intestinal transplantation in our center from 1989 to 2007. We report on 10-year posttransplant outcomes with (group 1, n=26) and without (group 2, n=9) a functional graft. Ten-year patient and graft survival rates were 53% and 36%, respectively. Most patients were studying or working, one third having psychiatric disorders. All patients in group 1 were weaned off parenteral nutrition with mostly normal physical growth and subnormal energy absorption. Graft histology from 15 late biopsies showed minimal abnormality. However, micronutrient deficiencies and fat malabsorption were frequent; biliary complications occurred in 4 patients among the 17 who underwent liver transplantation; median renal clearance was 87mL/min/1.73m2 . Four patients in group 1 experienced late acute rejection. Among the 9 patients in group 2, 4 died after 10years and 2 developed significant liver fibrosis. Liver transplantation and the use of a 3-drug regimen including sirolimus or mycophenolate mofetil were associated with improved graft survival. Therefore, intestinal transplantation may enable a satisfactory digestive function in the long term. The prognosis of graft removal without retransplantation is better than expected. Regular monitoring of micronutrients, early psychological assessment, and use of sirolimus are recommended.

Tacrolimus Trough Variability- Predictors and Outcomes in Pediatric Heart Transplantation

Tacrolimus is a narrow therapeutic index drug, requiring consistent levels to maximize solid organ transplant success while reducing adverse effects. High tacrolimus trough level variability (TTLV) is a significant predictor of late rejection in both kidney and liver transplant. We sought to describe the prevalence of high TTLV in our pediatric heart transplant (HT) population, and identify whether this variability is associated with patient specific factors and poor outcomes. Single center, retrospective study of HT patients from 1/2002 - 12/2018. Multi-organ recipients and retransplants were excluded. Records were reviewed for demographics, tacrolimus trough levels (TTLs) and outcomes (rejection, coronary vasculopathy, need for re-transplantation, death). Variability was calculated as the TTL standard deviation (SD) using each patient's TTLs from 1 year post-HT to last follow-up. High TTLV was defined as SD ≥3. Statistical analysis included Kruskal-Wallis, Chi-squared, and Wilcoxon rank sum testing. A total of 119 patients were included (male, 57%) with pre-HT diagnoses of congenital heart disease (57%) and cardiomyopathy (42%). The median age at HT was 2.7 yrs (IQR 0.8, 12.2) with a follow-up time post HT of 5.7 yrs (IQR 3.3, 9.9). A total of 6,344 TTLs were included, with a median of 33 TTLs/pt (IQR 14, 76). The median SD for the entire cohort was 3.1 (IQR 2.3, 4.0) with 55% of the population having a SD ≥3. Levels obtained from 1-5 yrs of age were found to have significantly greater variability (median SD 3.1 [IQR 2.4, 4.1]; p-value< 0.01) than 6-12 yrs (SD 2.5) and 12+ yrs (SD 2.5). After dichotomizing patients for higher variability (SD ≥ 3), there were no significant associations with patient specific factors including: sex, pre-HT diagnosis, pre-HT clinical course (acute vs chronic), age at HT, time with HT and Hollingshead Socioeconomic Score. High TTLV was associated with increased rejection treatment (74% vs 44%, p<0.01), higher frequency of coronary vasculopathy (23% vs 7%, p=0.02), and death (20% vs 6%, p=0.02). TTLV is high in pediatric HT recipients, especially in those < 5 yrs. Patients with a SD ≥3 experienced a higher frequency of poor outcomes including rejection, coronary vasculopathy and death.

Faster Time-to-Therapeutic Tacrolimus Level is Associated with Lower Risk of Cellular Rejection Early after Heart Transplantation

Faster time-to-therapeutic tacrolimus (TTT) levels is associated with lower rates of acute cellular rejection (ACR) in kidney and liver transplantation. Limited data have evaluated this relationship in heart transplant (HT) recipients. Single-center retrospective chart review of patients who received HT from January 1, 2014 to June 30, 2016. Multi-organ transplant recipients, re-transplants, and those who received induction therapy with either basiliximab or thymoglobulin were excluded. A therapeutic tacrolimus concentration was defined as a trough level between 8-15 ng/mL for two consecutive days. The primary outcome was the rates of 30-day ACR in patients who were < and ≥ the median TTT level. Serum creatinine values were also collected for the first 10 post-op days. From a database of 88 HT patients we evaluated 55 patients who did not receive induction therapy (median age=56 (49-65), 73% white, 71% had a VAD prior to HT). The median TTT level was 9 days; patients < the median (n=25) had similar characteristics as those ≥ the median (n=30). Rates of ACR were significantly lower in the < median group (8 v. 43%, p=0.005) (Figure), while serum creatinine values were similar between groups (p>0.05 for each day). Patients without ACR (n=40) had a median TTT level of 8 (6-9.5) days, compared to 10 (9-12) days in the ACR group (n=15) (p=0.01). A multivariate regression model found TTT ≥9 days to be significantly associated with early ACR after adjusting for age, gender, and VAD pre-HT (OR 9.84, 95% CI [1.86-52.90], p=0.007). Quickly achieving a TTT level reduces the risk of ACR early after HT without adversely affecting renal function.

Tacrolimus induces short-term but not long-term clinical response in inflammatory bowel disease.

Tacrolimus is a calcineurin inhibitor commonly used for prophylaxis of rejection in renal and liver transplantation. There are limited but favourable data regarding its possible use in patients with inflammatory bowel disease (IBD). To evaluate the efficacy and safety of tacrolimus in patients with IBD in clinical practice. We performed a retrospective, multicentre study in 22 centres in Spain. All adult patients who received oral tacrolimus for luminal or perianal IBD were included. Clinical response was assessed by Harvey-Bradshaw index and partial Mayo score after 3months. Perianal disease was evaluated by fistula drainage assessment. One hundred and forty-three patients were included (mean age 38years; 51% male; median disease duration 110months). In ulcerative colitis (UC) (n=58), the partial Mayo score decreased after 3months from median 6 to 3 (P=0.0001), whereas in Crohn's disease (CD) (n=85), the Harvey-Bradshaw index decreased after 3months from median 9 to 7 (P=0.011). In CD patients, blood tacrolimus concentrations during induction (>10ng/mL vs <10ng/mL; odds ratio 0.23, 95% CI 0.05-0.87) and the concomitant use of thiopurines (odds ratio 0.18, 95% CI 0.04-0.81) were associated with lower clinical disease activity at 3months. Of 62 patients with perianal disease, complete closure was observed in 8% (n=5) of patients with perianal fistulas, with 34% (n=21) showing partial response. Treatment was maintained for a median of 6months (IQR, 2-16). After a median clinical follow-up of 24months (IQR, 15-57), the rate of treatment-related adverse events was 34%, correlating with blood drug concentrations (P=0.021). Finally, 120 patients (84%) discontinued tacrolimus, usually due to absence or loss of response. Three patients (2%) were subsequently diagnosed with cancer. The overall rate of surgery was 39%, with a 33% colectomy rate in UC. Tacrolimus shows a clinical benefit in both CD and UC after 3months of treatment, but its long-term effectiveness and frequent adverse events remain relevant issues in clinical practice.

Steroid resistant rejection in liver transplantation; A single center study for risk factor and second line treatment

Steroid resistant rejection in liver transplantation; A single center study for risk factor and second line treatment

Procalcitonin versus C-reactive protein as indicator of acute rejection during orthotropic liver transplanation

Abstract Background Procalcitonin is the precursor for the hormone calcitonin (CT), which is found in the thyroid C cells and the pulmonary endocrine cells, it has a metabolic role in calcium homeostasis. In normal subjects, PCT is found in the blood at a very low concentration but during bacterial infection, there is more than 1,000 fold increase in its blood concentration as it is released by many other tissues as Liver, Spleen and Lungs. Aim of the Work to compare between procalcitonin and CRP as a markers of infection versus rejection in orthotropic liver transplantation; this comparison with their plasma level and the clinical difference during postoperative period. Patients and Methods This study was conducted on 25 patients aged 2-60 years old of both sexes scheduled for elective liver transplantation from living donors; after ethical committee approval and informed consent from patients and/or their first degree relatives, Ain Shams Specialized Hospitals. Results The study revealed that the normal course after liver transplantation for postoperative 28 days was (48%), rejection (16%), sepsis (24%) and rejection and sepsis (12%). Conclusion Procalcitonin is a good early diagnostic marker and is superior to CRP and WBCs in early detection of postoperative sepsis after orthotropic liver transplantation.

Effect of Hepatitis C Virus Treatment on Rejection Incidence and Severity in Post-Liver Transplant Recipients

Abstract Background and Aims HCV is a worldwide cause of chronic liver disease, particularly in Egypt where the most prevalent is genotype 4. HCV-associated cirrhosis is the most common indication for orthotopic liver transplantation (OLT) among adults. HCV infection remains a problem after transplantation, and recurrent hepatic infection is the leading cause of graft failure. Little is known about the long-term effects of direct acting antiviral therapy in patients after liver transplantation. We examined the incidence and severity of liver transplantation rejection in patients treated for HCV, post liver transplantation, with DAAs relative to the incidence and severity of liver transplantation rejection in patients treated for HCV, post liver transplantation, with Interferon based therapy and patients who didn’t receive any treatment for HCV after transplantation. Patients and Methods The study was conducted on 90 patients who had underwent liver transplantation between 2010 and 2017 at Ain Shams Center for Organ Transplantation (ASCOT) with a minimum follow up period of 6 months. Patients were divided into three groups: group I included 16 patients that didn’t receive antiviral treatment after liver transplantation, group II included 20 patients that had received interferon based therapy after liver transplantation and group III included 54 patients that had received direct acting antivirals after liver transplantation. Results Amongst group I, 2 patients (12.5%) developed acute graft rejection while in group II 2 patients (10%) developed chronic graft rejection and in group III 6 patients (11.11%) developed chronic rejection. In group I, all the patients (100%) had developed rejection that was diagnosed within one year of liver transplantation. In group II, 2 patients (100%) developed chronic graft rejection which occurred after one year of liver transplantation, one of them was on treatment with peg interferon and the other had already completed treatment. In group III, 2 patients (40%) had developed chronic rejection within one year of transplantation, while 4 patients (60%) had developed chronic rejection after one year of transplantation. One patient (16.67%) had developed rejection on treatment while 5 patients (83.33%) had developed rejection after the end of treatment. Conclusion It was found that the incidence of chronic rejection was more in patients that had received antiviral treatment after liver transplantation, however no difference was noted between DAAs and peg-interferon. Chronic rejection was found to be more common when treatment was given over one year after liver transplantation (6 cases) as compared to within the 1st year (2 cases). This may be related to the withdrawal of immunosuppression treatment after one year of transplantation and maintenance on monotherapy.

Early reduction of regulatory T cells is associated with acute rejection in liver transplantation under tacrolimus-based immunosuppression with basiliximab induction.

Regulatory T (Treg) cells are important in preventing acute rejection (AR) in solid organ transplantation, but the clinical relevance of the different kinetics early after liver transplantation (LT) in acute rejectors and non-rejectors is unclear. We analyzed peripheral blood samples of 128 LT recipients receiving basiliximab induction plus tacrolimus immunosuppression. Samples were obtained at pretransplant, D7, and D30 after LT. Frequency and phenotype of Tregs were analyzed by flow cytometry. The predictive value of Treg frequency at D7 was assessed for suspected acute rejection (SAR) and was validated for biopsy-proven AR (BPAR). We found that the frequencies of total and activated Tregs at D7 were significantly lower in recipients with SAR and BPAR. Treg was more reduced in BPARs by in vitro tacrolimus treatment in the presence of basiliximab. Moreover, an early reduction of Treg frequency in rejectors was associated with a greater increase in Treg apoptosis and further attenuated IL-2 signaling. D7 Treg frequency was an independent risk factor for SAR, which was also validated for BPAR. In conclusion, first-week peripheral blood Treg frequency correlates with AR after LT under tacrolimus-based immunosuppression, which needs to be proven in larger, geographically and clinically diverse populations.

Frailty Is Associated With Increased Rates of Acute Cellular Rejection Within 3 Months After Liver Transplantation.

Frailty, a state of decreased physiological reserve, has been associated with dysregulation of the immune system. We hypothesized that frailty is associated with differential rates of acute cellular rejection (ACR) in liver transplantation (LT) recipients. Our study included LT recipients from 2014 to 2016 who had a pre-LT frailty assessment using the liver frailty index (LFI). Frailty was defined as an LFI ≥4.5. ACR at 3months was ascertained from pathology reports, and immunosuppression regimens were collected from chart review. There were 241 LT recipients who were included: 46 (19%) were classified as frail before LT. Median tacrolimus trough levels, mycophenolate doses, and corticosteroid doses at discharge and 3months were similar between frail and nonfrail patients. Within 3months after LT, 7 (15%) frail patients versus 10 (5%) nonfrail patients experienced ACR (P=0.02). In the univariate analysis, frailty was associated with a higher odds of ACR at 3months (OR, 3.3; 95% confidence interval, 1.2-9.3; P=0.02). Bivariate analyses were conducted with covariates that were associated with ACR in the univariate analysis or that were previously associated with either frailty (age and female sex) or ACR (Model for End-Stage Liver Disease score and ascites), as well as relevant immunosuppression variables. In the bivariate analyses, frailty remained significantly associated with ACR at 3months with an odds ratio relatively similar to the unadjusted value. In conclusion, frailty is associated with an increased rate of ACR within 3months, despite similar immunosuppression regimens, suggesting that frailty should be considered in immediate post-LT management.

40. THE role of liver biopsy in the management of graft dysfunction at the Australian National Transplant Unit (ANLTU): A retrospective study of 77 cases

Background: Clinically liver allograft rejection in liver transplant (LT) presents with non-specific findings such as fever, jaundice and elevated liver function tests (LFTs). Histopathological assessment of liver biopsies is currently the gold standard for diagnosing graft rejection. Liver biopsy can be associated with complications such as bleeding and sepsis. Aim: To evaluate the role of liver biopsies in the diagnosis and management of liver rejection in patients who underwent LT at ANLTU in 2015 including (1) histological diagnoses of biopsies performed within 12-months post-LT; (2) changes in LFTs including alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) pre-and post-biopsy; and (3) changes to management pre-and post-biopsy. Methods: Retrospective clinical data was collected from RPAH databases. The histopathological diagnoses of biopsy slides were determined by slide review by 2–3 independent assessors according to the Banff criteria and previous biopsy reports. Data was analysed using IBM SPSS version 24. Results and conclusion: The most common indications for LT in the patient cohort (n=77) were alcoholic cirrhosis (26/120, 22%) and hepatitis C virus (23/120, 19%). 39% of patients (n=77) underwent at least one biopsy within 12-months post-LT with a total of 41 biopsies. Biopsy outcomes (n=41) were TCMR (76%), hepatitis C virus (7%) and cholestatic hepatitis (7%). Mean reduction (95% confidence interval) of ALT, GGT and ALP at 5±1 week post-biopsy in cases of TCMR (n=29) were 251 (138–363), 186 (82–290) and 182 (90–274) with p-values of <0.001, 0.001 and <0.001, respectively. In 15 (45%, n=31) cases of TCMR, patients received intravenous (IV) methylprednisone pulsing following biopsy, 93% (n=15) of which had moderate or severe TCMR. The significant reduction in LFTs post-biopsy and management with IV methylprednisolone following biopsy-confirmed TCMR suggest liver biopsies may play a key role in the diagnosis and management of TCMR.

41. Banff global assessment and rejection activity index severity grading criteria for T-Cell Mediated Rejection (TCMR) in liver transplantation are strongly correlated

41. Banff global assessment and rejection activity index severity grading criteria for T-Cell Mediated Rejection (TCMR) in liver transplantation are strongly correlated

RETRACTED ARTICLE: Approaching treatment for immunological rejection of living-donor liver transplantation in rats

BackgroundThe anti-immunological rejection therapy for small-for-size syndrome (SFSS) after live donor liver transplantation (LDLT) play a central role in keeping graft survival. The hepatocyte number and grafts function has undergone real-time changes with the proliferation and apoptosis of the grafts after reperfusion. Lacking an accurate and effective treatment regiments or indicators to guide the use of immunosuppressive drugs in SFS liver transplantation has made immunotherapy after SFS liver transplantation an urgent problem to be solved. Herein, we established small-for-size (SFS) and normal size liver transplantation model in rats to explore the effective indicators in guiding immunotherapy, to find an effective way for overcoming SFSS.MethodsLewis rats (donors) and BN rats (recipients) were used to mimic allograft liver transplantation and treated with tacrolimus. Local graft immune response was analyzed through haematoxylin and eosin and immunohistochemistry. Flow cytometry was used to assess the overall immune status of recipient. The pharmacokinetics mechanism of immunosuppressive drugs was explored through detecting CYP3A2 expression at mRNA level and protein levels.ResultsThe results showed the local immune reaction of SFS grafts and systemic immune responses of recipient were significantly increased compared with those in normal size grafts and their recipient at four days after liver transplantation. Regression equation was used to regulate the tacrolimus dose which not only controlled tacrolimus serum concentration effectively but alleviated liver damage and improved survival rate.ConclusionsThis study showed that AST level and tacrolimus serum concentrations are effective indicators in guiding immunotherapy. Regression equation (TD = − 0.494TC-0.0035AST + 260.487) based on AST and tacrolimus serum concentration can be used as a reference for adjustment of immunotherapy after SFS liver transplantation, which is applicable in clinical practice.

Tacrolimus therapeutic efficacy in post-liver transplant patients with Cytochrome P450 3A5 (CYP3A5) genetic polymorphisms.

Genetic polymorphisms of CYP3A5 have been pointed out as factors that influenciates tacrolimus immunosuppressive efficacy in post liver transplant patients. This study aims to review the literature on the influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphisms of tacrolimus in post-liver transplant patients. This study is a literature review. A combination of the descriptors "tacrolimus", "liver transplant", "cytochrome P-450 CYP3A inhibitors" and "genetic polymorphism" were used in the databases PubMed, Cochrane Library, Scopus and Scielo, being evaluated only studies between 2009 and 2019 in English, Portuguese or Spanish. A total of six studies, each from a different population were summarized. Initially, the pharmacological aspects of tacrolimus were discussed, including details on its pharmacodynamics, pharmacokinetics and toxicity After that, we analyzed the studies that correlates CYP3A5 genetic polymorphisms and tacrolimus efficacy, including the ethnical specifications and the general limittions of the studies. The CYP3A5 polymorphisms have pointed to alterations in the metabolism of tacrolimus according to the ethnic and populational genotype, specially the *1 and *3*3 alleles, reflecting in the need for dose adjustment and also in post liver transplant rejection.

CD47 blockade alleviates acute rejection of allogeneic mouse liver transplantation by reducing ischemia/reperfusion injury

Despite advances in immunosuppressive therapies, acute rejection response is still a serious concern especially in the early phase after liver transplantation. This study aimed to evaluate whether blocking the TSP1-CD47 signaling pathway could attenuate the acute rejection after liver transplantation. An allogeneic mouse orthotopic liver transplantation model (Balb/c→C3H) with prolonged cold ischemic phase was used to induce severe IRI and lethal acute rejection. CD47mAb or isotype matched-control IgG2a was administered to donor liver during graft perfusion. Recipients were sacrificed at 1d, 3d, 5d and 7d after reperfusion. Blood samples were collected to evaluate serum alanine aminotransferase, total bilirubin, HMGB-1,TNF-α, IL-2 and INF-γ level. Flow cytometric analysis was used to detect the strength of innate and adaptive immune response. Liver tissue was obtained for HE, TUNEL staining and F4/80 immumohistochemical staining. Moreover, we conducted a mixed lymphocyte reaction treated with IgG2a or CD47mAb. Mice in CD47mAb-treated group demonstrated improved survival and significantly lower increase in Suzuki score, apoptosis index, acute rejection index, serum alanine aminotransferase, total bilirubin, HMGB-1, TNF-α, IL-2, INF-γ level and the degree of Kupffer cells' activation especially in the early phase of acute rejection. In addition, Pearson's correlation analysis confirmed significant correlation between Suzuki score/ALT and acute rejection index. The in vitro inhibition assay showed that CD47 blockade couldn’t directly inhibit recipient lymphocyte proliferation. Based on the evidence that TSP1-CD47 signaling blockade with CD47mAb could alleviate acute rejection by reducing the extent of IRI after liver transplantation indirectly, this study provided a basis for new interventions and management methods to support better transplant outcomes.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene polymorphisms in liver transplant donors and impact on acute cellular liver transplant rejection.

The PTPN22 gene encodes the lymphoid protein tyrosine phosphatase involved in regulation the immune response. The single nucleotide polymorphisms (SNPs) rs1217388, rs1310182, rs2476601, and rs2488457 are located within the PTPN22 gene. We investigated whether these SNPs in liver transplant donors are associated with acute cellular rejection in the recipients. The SNPs were analyzed in donors (n = 104) of recipients who did not develop an acute cellular rejection and in donors (n = 53) of corresponding recipients developing an acute cellular rejection. No significant differences in genotype and allele frequencies of these SNPs were detected in either of the group. Our data suggest that these SNPs in liver transplant donors have no impact on the susceptibility of acute cellular liver transplant rejection.

2402 A Rare Case of IPEX Syndrome With Hepatic Complications

INTRODUCTION: Immunodysregulation, polyendocrinopathy and enteropathy X-linked (IPEX) Syndrome is a rare autoimmune illness affecting only males starting in the early few months of life. It can be associated with autoimmune hepatitis among other systemic ailments and ultimate treatment is immunosuppression or bone marrow transplant. We present a case of undiagnosed IPEX Syndrome leading to liver failure requiring eventual liver transplantation. CASE DESCRIPTION/METHODS: A 19 year-old male patient had undergone a liver transplant at age 2 for suspected autoimmune hepatitis resulting in acute liver failure. No specific cause was identified at time of diagnosis. He remained on chronic immunosuppression thereafter, eventually progressing to chronic active autoimmune hepatitis in the transplanted liver. He was diagnosed with IPEX Syndrome at age 16, for which he underwent a bone marrow transplant. He presented to the hospital with neutropenia, and hepatology was consulted for liver transplant rejection in light of mild transaminitis. On admission, vital signs were normal and pertinent labs include: AST/ALT 50/74 units/L, Alkaline Phosphatase 811 IU/L, Albumin 3.4 g/dL, WBC 0.6 × 109 cells/L. He reportedly had multiple episodes of acute rejection in the past which were treated with steroids. Chronically, he was on mycophenolate mofetil, tacrolimus, and prednisone. His liver biopsy did not show evidence of acute rejection, but suggested chronic rejection and liver fibrosis. A prior liver biopsy had suggested autoimmune hepatitis, but no evidence of a flare on current biopsy. He was continued on his current immunosuppression regimen, and he was subsequently discharged home. DISCUSSION: Due to its rarity, incidence of IPEX syndrome is not entirely known, but is estimated to be 1 in 1,609,490. Generally, it is diagnosed in infancy and is often fatal. Our case is unique as the diagnosis was missed for more than a decade during which period the patient had even received a liver transplant for autoimmune hepatitis. Autoimmune hepatitis reportedly occurs in 20% of patients with IPEX Syndrome. There are currently no reports of liver failure requiring liver transplant in such scenarios. The fact that our patient developed recurrent autoimmune hepatitis in the transplanted liver highlights the underlying defect in his genetic disorder. This case should serve as a reminder to clinicians to consider IPEX syndrome in the differential for early onset autoimmune hepatitis, as early diagnosis could reduce significant morbidity.

Retraction: The Ratio of Circulating Regulatory T Cells (Tregs)/Th17 Cells Is Associated with Acute Allograft Rejection in Liver Transplantation.

Retraction: The Ratio of Circulating Regulatory T Cells (Tregs)/Th17 Cells Is Associated with Acute Allograft Rejection in Liver Transplantation.

The proportion of CD19+CD24hiCD27+ regulatory B cells predicts the occurrence of acute allograft rejection in liver transplantation.

Regulatory B cells (Bregs) play an essential role in inflammation and transplant tolerance. Several studies have reported a decreased number of Bregs in renal transplant patients with graft rejection. However, little is known about their role in the liver alloresponse. To investigate whether the circulating Bregs have been associated with acute allograft rejection (AR) in liver transplantation patients, 19 patients receiving liver allografts from donation after cardiac death (DCD) donors were retrospectively studied. The postoperative proportions of circulating CD19+CD24hiCD38hi transitional Bregs (tBregs) and CD19+CD24hiCD27+ memory Bregs (mBregs) in patients diagnosed with AR (AR group) and other patients with stable allograft liver function (SF group) were evaluated using flow cytometry (FCM) analysis. Results showed that while no significant changes were found regarding both the tBreg and mBreg, proportions across all time points in the SF group, the AR group showed significantly decreased proportions of mBregs. All of the five AR patients responded fine to the treatments, and the proportions of mBregs increased significantly after anti-rejection therapies. In addition, AR was suspected in four recipients, but gradually they were diagnosed with hemolytic or obstructive jaundice and showed no decrease in the proportion of mBregs. For the first time, our results suggested the potential role of a decreased proportion of circulating mBregs in predicting AR in patients with post liver transplantation.