Spontaneous restoration of transplantation tolerance after acute rejection.
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ABSTRACT:
SUBMITTER: Miller ML
PROVIDER: S-EPMC4498267 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection.
| S-EPMC5377586 | biostudies-literature
Project description:Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection. B10.BR mice were used as donors and B10.D2 mice were used as recipients. Liver allo-transplantation surgery on the mice was performed in this combination. Three mice from each group were sacrificed, and the liver grafts were removed on days 5, 8, 14 and 100 after transplantation. Total RNA, including miRNA was isolated. 100ng of total RNA was labeled by Cy3 and used as probe for hybridization to the microarray.
2014-10-21 | E-GEOD-52164 | biostudies-arrayexpress
Project description:Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection.
2014-10-21 | GSE52164 | GEO
Project description:Treatment of acute rejection (AR) following kidney transplantation has improved in recent years, but there are still limitations to successful outcomes. This review article covers literature in regard to recipient and donor genetics of AR kidney and secondarily of liver allografts. Many candidate gene and some genome-wide association studies (GWASs) have been conducted for AR in kidney transplantation. Genetic associations with AR in kidney and liver are mostly weak, and in most cases, the associations have not been reproducible. A limitation in the study of AR is the lack of sufficiently large populations that account for population stratification to study the AR phenotype which in this era occurs in <10% of transplants. Furthermore, the AR phenotype has been difficult to define and the definitions of classifications have evolved over time. Literature related to the pharmacogenomics of tacrolimus is robust and has been validated in many studies. Associations between gene expression and AR are emerging as markers of outcomes and AR classification. In the future, combinations of pretransplant genotype for AR risk prediction, genotype-based immune suppressant dosing, and pharmacogenomic markers to select AR maintenance or treatment and expression markers from biopsies may provide valuable clinical tools for guiding treatment.
| S-EPMC6260834 | biostudies-literature
Project description:Acute cellular rejection (ACR) is a common complication following lung transplantation (LTx), affecting almost a third of recipients in the first year. Established, comprehensive diagnostic criteria exist but they necessitate allograft biopsies which in turn increases clinical risk and can pose certain logistical and economic problems in service delivery. Undermining these challenges further, are known problems with inter-observer interpretation of biopsies and uncertainty as to the long-term implications of milder or indeed asymptomatic episodes. Increased risk of chronic lung allograft dysfunction (CLAD) has long been considered the most significant consequence of ACR. Consensus is lacking as to whether this applies to mild ACR, with contradictory evidence available. Given these issues, research into alternative, minimal or non-invasive biomarkers represents the main focus of research in ACR. A number of potential markers have been proposed, but none to date have demonstrated adequate sensitivity and specificity to allow translation from bench to bedside.
| S-EPMC7186718 | biostudies-literature
Project description:ObjectiveTo evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses.MethodsWe conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time.ResultsThere were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P<.001), with median intrapartum creatinine of 3.90 compared with 1.15 mg/dL (P<.001). Conversely, only patients with preeclampsia had a significant increase in proteinuria from baseline. Although there were no significant differences in maternal outcomes, graft loss within 2 years postpartum (42% vs 10%) and long-term graft loss (73% vs 35%) were significantly increased in recipients who experienced acute rejection (P<.001 for both). The frequency of delivery before 32 weeks of gestation was 53% with acute rejection and 20% with preeclampsia. After controlling for hypertension and immunosuppressant use, acute rejection was associated with higher frequency of delivery at less than 32 weeks of gestation (adjusted odds ratio 4.04, 95% CI 1.10-15.2).ConclusionIn pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients.Funding sourceThe Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals.
| S-EPMC8141043 | biostudies-literature
Project description:Acute allograft rejection is a serious and life-threatening complication of organ transplantation. Th17 cells induced inflammation has been described to play an important role in allograft rejection. Since there is a plenty of evidence indicating that transcriptional factor BATF regulates the differentiation of Th17 and follicular T helper cells both in vitro and in vivo, we investigated whether is BATF involved in acute rejection and allograft survival by injecting lentivirus containing BATF shRNA through tail vein before the cardiac transplantation operation. We found that the allograft survival time of the mice treated with BATF shRNA was significantly prolonged compared with that of negative shRNA treated group and the control group. Further pathological analysis revealed that the BATF shRNA treatment group had significantly lower rejection degree than the negative shRNA group, while there was no significant difference between the negative shRNA group and the control group. Furthermore, flow cytometry analysis and quantitative polymerase chain reaction and enzyme-linked immuno sorbent assay were used to determine the proportion of T helper cells, the expression of specific transcription factor and the inflammatory cytokines respectively. Data showed that BATF regulated Th17 and Treg responses during allograft rejection. And BATF inhibition led to reduction of the expression level of Rorγ-t and enhancement of the Foxp-3. In addition, cytokines IL-17A and IL-4 were found decreased. This may indicate BATF as a novel therapy target for treatment of acute allograft rejection.
| S-EPMC5009413 | biostudies-literature
Project description:ImportanceAcute rejection is one of the most frequent complications in facial transplantation, with potentially severe consequences for the recipient if overlooked. Clinical signs, such as erythema or edema, are helpful to diagnose acute rejection in the early follow-up stage; however, it is not well known whether these clinical signs remain reliable markers of acute rejection beyond the second posttransplant year.ObjectiveTo determine the diagnostic value of clinical signs of acute rejection after facial transplantation over time.Design, setting, and participantsA retrospective, single-center cohort study was conducted of patients who underwent facial transplantation at Brigham and Women's Hospital between April 2009 and October 2014, with up to an 8-year follow-up. Medical records were reviewed until September 30, 2017. The medical records from 104 encounters with 7 patients who underwent partial or full facial transplantation were analyzed for symptoms of rejection, immunosuppressive therapy, and histopathologic findings.Main outcomes and measuresThe occurrence of 5 clinical signs of acute rejection were evaluated: erythema, edema, exanthema, suture line erythema, and mucosal lesions. Odds ratios (ORs) were calculated to determine the statistically significant association of these signs with the histopathologic diagnosis of rejection. In addition, tacrolimus blood levels, as a surrogate marker of immunosuppressive therapy, were evaluated.ResultsOf the 7 patients included in the study, 5 were men. The mean follow-up was 66 months (range, 35-101). Of 104 clinical encounters, 46 encounters (44.2%) represented rejection episodes and 58 encounters (55.8%) represented no-rejection episodes. Beyond 2 years posttransplantation, only erythema (OR, 6.53; 95% CI, 1.84-20.11; P = .004) and exanthema (OR, ∞; 95% CI, 2.2-∞; P = .004) were demonstrated to be reliable clinical signs of acute rejection in facial transplantation. There was also a statistically significant association of subtherapeutic tacrolimus levels with late rejection episodes (OR, 3.79; 95% CI, 1.25-12.88; P = .03). In addition, the occurrence of subclinical rejection was more frequent during later follow-up times (7 [24.1%] late rejections vs 1 [5.9%] early rejection). Five of 8 subclinical rejections (62.5%) were associated with subtherapeutic tacrolimus levels.Conclusions and relevanceClinical signs of acute rejection in facial transplantation appear to be of limited diagnostic value, particularly after the second postoperative year. Until alternative biomarkers for rejection are identified, protocol skin biopsies will remain necessary for guiding assessments of allograft rejection.Level of evidence3.
| S-EPMC6646986 | biostudies-literature
Project description:In this study, we examined transcriptional profiles from 3 different microarray platforms, across 103 peripheral blood samples with and without acute rejection, to find a critical gene-set for the diagnosis of acute renal rejection that matched biopsy diagnosis, irrespective of patient demographics, clinical confounders, concomitant infection, immunosuppression usage or sample processing methods. We hypothesized that changes in peripheral blood expression profiles correlate with biopsy-proven rejection, and that these changes could be used as biomarkers for the diagnosis and prediction of acute rejection. We performed cross-sectional microarray analysis of 103 matched peripheral blood samples collected at a single time point, timed with a biopsy where acute rejection was either confirmed as present (60 AR samples) or absent (62 STA samples). The samples were hybridized to one of 3 microarray platforms: Affymetrix (n=75 the 54K HG-U133_Plus2 Array), Agilent (n=26, 44K oligo Array) and cDNA array (n=21, ~30K cDNA). Of 103 samples, 14 were used on both Affy and Agilent arrays; 1 was used in cDNA and Agilent array and 2 were used across 3 array platforms. Microarray data generated from 3 array platforms were cross-compared, by mapping common and overlapping transcripts to Human Gene Organization (HUGO) gene names. Significant gene lists on each platform were identified using Significant Analysis of Microarray (SAM, ref) with a common significance threshold of a false discovery rate (FDR) of <10%.This set contains the data for samples hybridized to Affymetrix arrays. Disease State: Acute Rejection (AR#sampleid) or Stable (S#sampleid) samples. This dataset is part of the TransQST collection.
2012-12-26 | E-GEOD-14346 | biostudies-arrayexpress
Project description:Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.
| S-EPMC4148014 | biostudies-literature