Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

De Novo Donor-Specific HLA Antibody Formation in Two Patients With Crigler-Najjar Syndrome Type I Following Human Hepatocyte Transplantation With Partial Hepatectomy Preconditioning.

ABSTRACT: Clinical hepatocyte transplantation is hampered by low engraftment rates and gradual loss of function resulting in incomplete correction of the underlying disease. Preconditioning with partial hepatectomy improves engraftment in animal studies. Our aim was to study safety and efficacy of partial hepatectomy preconditioning in clinical hepatocyte transplantation. Two patients with Crigler-Najjar syndrome type I underwent liver resection followed by hepatocyte transplantation. A transient increase of hepatocyte growth factor was seen, suggesting that this procedure provides a regenerative stimulus. Serum bilirubin was decreased by 50%, and presence of bilirubin glucuronides in bile confirmed graft function in both cases; however, graft function was lost due to discontinuation of immunosuppressive therapy in one patient. In the other patient, serum bilirubin gradually increased to pretransplant concentrations after ≈600 days. In both cases, loss of graft function was temporally associated with emergence of human leukocyte antigen donor-specific antibodies (DSAs). In conclusion, partial hepatectomy in combination with hepatocyte transplantation was safe and induced a robust release of hepatocyte growth factor, but its efficacy on hepatocyte engraftment needs to be evaluated with additional studies. To our knowledge, this study provides the first description of de novo DSAs after hepatocyte transplantation associated with graft loss.

SUBMITTER: Jorns C

PROVIDER: S-EPMC5061095 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Recommendations for pregnancies in patients with crigler-najjar syndrome.

Project description:During pregnancy, the developing foetus in mothers with Crigler-Najjar type 1 and 2 is exposed to raised levels of unconjugated bilirubin, with the risk of neurotoxicity. We describe two pregnancies in a patient with Crigler-Najjar type 2, who was carefully monitored prior to and during pregnancy and phototherapy adjusted to maintain serum bilirubin levels below 200 ?mol/l and the bilirubin/albumin molar ratio below 50%. Both pregnancies resulted in normal delivery of healthy infants who had normal neurological development. A review of all reported pregnancies in Crigler-Najjar patients and a set of recommendations are presented.

| S-EPMC3575037 | biostudies-literature

Novel combined UGT1A1 mutations in Crigler Najjar Syndrome type I.

Project description:BackgroundUridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), which is the major UGT1 gene product, is located on chromosome 2q37. The expression of UGT1A1 is relatively managed by a polymorphic dinucleotide repeat inside the promoter TATA box consisting of 5-8 copies of a TA repeat. A (TA) 6TAA is considered as the wild type. The A (TA) 7TAA allele has been identified as the most frequent allele in the Caucasian populations while A (TA) 8TAA allele remains the rarest allele worldwide in North Africa, including the Arab populations.MethodsThe spectrum of UGT1A1 genetic mutations in seventeen Tunisian children affected by persistent unconjugated hyperbilirubinemias is represented in addition to their relatives, notably parents, sisters, and brothers. Tunisian children, from 16 unrelated families as well as a 17th family without CN1 affected child, were originated from the West Center of Tunisia. The promoter region and coding exons of the UGT1A1 were PCR amplified, subsequently subjected to Sanger sequencing.ResultsThe frequencies of genotypes in CN1 patients were as follows (TA) (7/7) (12/17: 70.6%) and (TA) (8/8) (5/17: 29.4%). All patients harbored the c.1070A>G mutation of exon 3 (UGT1A1*16) in the homozygous state. Among relatives of our patients (n = 16), who were all heterozygotes for UGT1A1*16, 13/16 (81.25%) had a heterozygous state for UGT1A1∗1/UGT1A1∗28 or (TA) (6/7) and, 18.75% (3/16) were heterozygous for UGT1A1∗28/UGT1A1∗37 or (TA) (7/8) of the promoter polymorphisms.ConclusionUGT1A1*16 accompanied with UGT1A1*28 or UGT1A1*37 had a specific geographic and ethnic distribution for CN pathogenesis in this Tunisian cohort.

| S-EPMC9169181 | biostudies-literature

Non-Complement-Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival.

Project description:C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity >6237 and >10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P<0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.

| S-EPMC4731103 | biostudies-literature

Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier.

Project description:Background and aimsWe describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years.Approach and resultsUnbound ("free") bilirubin (Bf ) was measured in patient sera to characterize the binding of unconjugated bilirubin (BT ) to albumin (A) and validate their molar concentration ratio (BT /A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep BT /A at least 30% below intravascular BT binding capacity (i.e., BT /A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (Lf ) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to BT (R2 = 0.71) and BT /A (R2 = 0.76), and Bf as a percentage of BT correlated inversely to the bilirubin-albumin equilibrium association binding constant (R2 = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 ± 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak BT ≥ 30 mg/dL and BT /A ≥ 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 µW/cm2 •nm for 9.2 ± 1.1 hours/day kept BT and BT /A within safe limits throughout childhood, but BT increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized BT and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe.ConclusionSeven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.

| S-EPMC7909716 | biostudies-literature

Eplet mismatches associated with de novo donor-specific HLA antibody in pediatric kidney transplant recipients.

Project description:BackgroundOptimizing amino acid (eplet) histocompatibility at first transplant decreases the risk of de novo donor-specific antibody (dnDSA) development and may improve long-term graft survival in pediatric kidney transplant recipients (KTR). We performed a retrospective analysis of pediatric KTR and their respective donors to identify eplets most commonly associated with dnDSA formation.MethodsEplet mismatch analysis was performed in a cohort of 125 pediatric KTR-donor pairs (2006-2018). We determined the prevalence of each eplet mismatch and quantified the percentage of exposed patients who developed dnDSA for each mismatched eplet.ResultsRecipient median age was 14 (IQR 8-17) years with a racial distribution of 42% Black, 48% Caucasian, and 5.6% Middle-Eastern. Median eplet load varied significantly by recipient race, Black 82 (IQR 58-98), White 60 (IQR 44-81) and Other 66 (IQR 61-76), p = 0.002. Forty-four percent of patients developed dnDSA after median 37.1 months. Compared to dnDSA- patients, dnDSA+ patients had higher median eplet load, 64 (IQR 46-83) vs. 77 (IQR 56-98), p = 0.012. The most common target of dnDSA were eplets expressed in HLA-A*11 and A2 in Class I, and HLA-DQ6 and DQA5 in Class II. The most commonly mismatched eplets were not the most likely to result in dnDSA formation.ConclusionsIn a racially diverse population, only a subset of eplets was linked to antibody formation. Eplet load alone is not a sufficient surrogate for eplet immunogenicity. These findings illustrate the need to optimize precision in donor selection and allocation to improve long-term graft outcomes. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

| S-EPMC8602732 | biostudies-literature

Partial Hepatectomy Induced Long Noncoding RNA Inhibits Hepatocyte Proliferation during Liver Regeneration.

Project description:Liver regeneration after partial hepatectomy (PHx) is a complex and well-orchestrated biological process in which synchronized cell proliferation is induced in response to the loss of liver mass. To define long noncoding RNAs (lncRNAs) that participate in the regulation of liver regeneration, we performed microarray analysis and identified more than 400 lncRNAs exhibiting significantly altered expression. Of these, one lncRNA, LncPHx2 (Long noncoding RNA induced by PHx 2), was highly upregulated during liver regeneration. Depletion of LncPHx2 during liver regeneration using antisense oligonucleotides led to a transient increase in hepatocyte proliferation and more rapid liver regeneration. Gene expression analysis showed that LncPHx2 depletion resulted in upregulation of mRNAs encoding proteins known to promote cell proliferation, including MCM components, DNA polymerases, histone proteins, and transcription factors. LncPHx2 interacts with the mRNAs of MCM components, making it a candidate to regulate the expression of MCMs and other genes post-transcriptionally. Collectively, our data demonstrate that LncPHx2 is a key lncRNA that participates in a negative feedback loop modulating hepatocyte proliferation through RNA-RNA interactions.

| S-EPMC4514479 | biostudies-literature

Partial hepatectomy?induced upregulation of SNHG12 promotes hepatocyte proliferation and liver regeneration.

Project description:Following partial hepatectomy (PH), the complex process of liver regeneration is initiated, which encompasses the synchronized induction of hepatocyte proliferation. Hepatocyte proliferation can be regulated by multiple stimuli, including long non?coding RNAs (lncRNAs) and Wnt/??catenin signaling, although the underlying mechanism of lncRNA/Wnt in liver regeneration remains unclear. In the present study, a liver regeneration?associated functional lncRNA was identified, and its function was delineated in vitro and in vivo; lncRNA small nucleolar RNA host gene 12 (SNHG12) was revealed to be upregulated at various time?points after 2/3 PH. The expression of SNHG12 was also increased in normal liver cell lines treated with different concentrations of hepatocyte growth factor (HGF). Functionally, SNHG12 enhanced hepatocyte proliferation in vitro and in vivo, and the liver/body weight ratio of SNHG12?overexpressing mice was significantly higher than that of the control mice. Overexpression of SNHG12 promoted the activation of Wnt/??catenin signaling in hepatocytes. Furthermore, specific inhibition of Wnt/??catenin signaling significantly attenuated SNHG12?induced hepatocyte proliferation and the affected liver/body weight ratio. Collectively, the results of the present study indicated that SNHG12 contributes to liver regeneration by activating Wnt/??catenin signaling. Therefore, drugs that regulate the SNHG12/Wnt axis may be beneficial for liver regeneration following PH.

| S-EPMC7003022 | biostudies-literature

Clinical impact of complement (C1q, C3d) binding De Novo donor-specific HLA antibody in kidney transplant recipients.

Project description:IntroductionComplement binding activity of donor-specific HLA antibodies (DSA) has been suggested as a new tool to stratify immunologic risk in kidney transplantation (KT). The objective of this study was to evaluate the clinical implication of C1q/C3d binding activity of de novo DSA (dnDSA) in KT recipients.Material and methodsA total of 161 pretransplant DSA-negative recipients were monitored for dnDSA at the time of biopsy. C1q/C3d binding activities of dnDSA were assessed using C1qScreen assay (One lambda, USA) and Lifecodes C3d detection assay (Immucor, USA), respectively. Clinical outcomes including biopsy-proven antibody mediated rejection (AMR), C4d detection and post-biopsy graft survival were investigated.ResultsDe-novo DSAs were detected in fifty-four (33.5%) patients (HLA class I only, n = 19; class II only, n = 29; both class I and II, n = 6). Of them, complement binding activities were detected in 26 (48.1%) patients, including 17 C1q+ and 24 C3d+ patients. Both C1q and C3d positivity were associated with increased mean fluorescence intensity values of dnDSA. Complement binding activity of dnDSA enhanced the incidence of AMR (25.0% in C1q-C3d-, 36.4% in C1q+/C3d- or C1q-/C3d+, and 60.0% in C1q+/C3d+ patients) (P <0.001). The incidence of AMR was not different between patients with C1q+ and those with C3d+ dnDSA (64.7%, 11/17 versus 45.8%, 11/24, P = 0.238). In comparison between C1q and C3d assay according to HLA specificity, C1q+ HLA class I ± II dnDSA was the best predictor for AMR (odds ratio: 27.2). C1q+/C3d+ dnDSA was associated with more C4d deposition in allograft tissue and inferior post-biopsy graft survival. Clinical outcomes were not significantly different between C1q+ and C3d+ dnDSA-positive patients.ConclusionDetection of complement binding activity using both C1q and C3d assays can be a further prognostic marker for predicting AMR and allograft outcome in dnDSA+ kidney transplant patients.

| S-EPMC6235372 | biostudies-literature

Spectrum of UGT1A1 Variations in Chinese Patients with Crigler-Najjar Syndrome Type II.

Project description:Crigler-Najjar Syndrome type II (CNS-II) is an autosomal recessive hereditary condition of unconjugated hyperbilirubinemia without hemolysis, with bilirubin levels ranging from 102.6 μmol/L to 342 μmol/L. CNS-II is caused by a deficiency of UDP-glucuronyl transferase (UGT), which is encoded by the UDP-glucuronyl transferase 1A1 gene (UGT1A1). In East Asian populations, the compound homozygous UGT1A1 G71R and Y486D variants are frequently observed in cases with bilirubin levels exceeding 200 μmol/L. In this study, we investigated the spectrum of UGT1A1 variations in Chinese CNS-II patients. We sequenced the enhancer, promoter, and coding regions of UGT1A1 in 11 unrelated Chinese CNS-II patients and 80 healthy controls. Nine of these patients carried variations that are here reported for the first time in CNS-II patients, although they have been previously reported for other types of hereditary unconjugated hyperbilirubinemia. These individual variations have less influence on UGT activity than do the compound homozygous variation (combination of homozygous G71R variant and Y486D variant). Therefore, we propose that the spectrum of UGT1A1 variations in CNS-II differs according to the bilirubin levels.

| S-EPMC4439166 | biostudies-literature

Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome.

Project description:BackgroundInherited unconjugated hyperbilirubinemia is caused by variants in the gene UGT1A1 leading to Gilbert's syndrome and Crigler-Najjar syndrome types I and II. These syndromes are differentiated on the basis of UGT1A1 residual enzymatic activity and its affected bilirubin levels and responsiveness to phenobarbital treatment.Case presentationIn this report, we present a boy with Crigler-Najjar syndrome type II with high unconjugated bilirubin levels that decreased after phenobarbital treatment but increased in adolescence. Four different UGT1A1 gene variants have been identified for this patient, of which one is novel (g.11895_11898del) most likely confirming diagnose molecularly.ConclusionsThe presented case highlights the challenges encountered with the interpretation of molecular data upon identification of multiple variants in one gene that are causing different degree reducing effect on enzyme activity leading to several clinical conditions.

| S-EPMC6169020 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data