Ontology highlight
ABSTRACT:
PROVIDER: PRJNA106581 | ENA |
REPOSITORIES: ENA
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Project description:Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating CD4+T-bet+ T cells, CD8+T-bet+ T cells, and CD4+FOXP3+ regulatory T cells were reduced. Single cell RNA sequencing revealed a unique expression profile in immune cells in the skin of baricitinib plus CsA treated mice, including decreased inflammatory neutrophils and increased CCR2- macrophages. In a fully major histocompatibility mismatched mismatched heart allograft model, baricitinib plus CsA prevented graft rejection for the entire 28-day treatment period compared with 9 days in controls. Our findings establish that the combination of baricitinib and CsA prevents rejection in allogeneic skin and heart graft models and supports the study of JAK inhibitors in human solid organ transplantation.
2024-06-13 | GSE269828 | GEO
Project description:Selecting the right immunosuppressant to ensure rejection-free outcomes poses unique challenges in pediatric liver transplant (LT) recipients. A molecular predictor can comprehensively address these challenges. Although early acute cellular rejection (ACR) is mediated by cytotoxic T-cells, late rejection also includes antibody-mediated damage in addition to cell-mediated injury. Currently, there are no well-validated blood-based biomarkers for pediatric LT recipients either pre- or post- transplant. Here, we discover and validate separate pre- and post- transplant molecular signatures of LT outcome from whole blood transcriptomes. Using an integrative machine learning approach, we combine transcriptomic data with the high-quality reference human protein interactome network to identify differentially regulated functional sub-components of the network, or “network module signatures”, which drive ACR. Unlike gene signatures, our approach is inherently multivariate, more robust to replication and captures the structure of the underlying molecular network, encapsulating additive effects. We also identify, in a patient-specific manner, network module signatures that can be targeted by current anti-rejection drugs and other mechanisms that can be repurposed. Overall, our approach can enable personalized adjustment of drug regimens for the dominant targetable pathways in pre- and post- LT in children.
2022-04-11 | GSE200340 | GEO
Project description:Transplant rejection is a major factor limiting allograft survival. CircRNAs are reported to be strongly associated with various diseases pathogenesis. However, the potential role of circRNAs in cardiac transplant rejection are rarely reported. Here, differentially expressed mRNAs and circRNAs were determined by microarrays in allogeneic cardiac allografts. Functional analysis was then performed and a full-scale functional blueprint of the circRNA-associated-ceRNA networks was constructed. Among the circRNA networks, circ23123 expression was negatively linked with cytolytic molecules of CD8+ T cells by targeting miR155-SOCS1 axis. We illustrated a new comprehensive view of circRNAs and their potential functional impact in cardiac transplantation. It may provide a prospective for therapeutic strategy on organ transplant rejection in the future.
2020-12-16 | GSE163261 | GEO
Project description:Acute cellular rejection occurs frequently during the first few weeks following liver transplantation. During this period its molecular phenotype is confounded by pro-inflammatory events elicited by surgery, ischemia-reperfusion injury and early post-transplant complications. To unambiguously define the molecular profile associated with rejection we collected sequential biological specimens from liver transplant patients at least 3 years after transplantation who developed rejection while enrolled in trials of intentional immunosuppression withdrawal Transcriptomic RISET 2.0 chips were employed using portal blood vein from 37 liver trasplant patients.Two timepoints were selected: before immunosupressive weaning and rejection time point.
2016-06-01 | E-GEOD-70305 | biostudies-arrayexpress
Project description:Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. Groups differed in median time post-transplant e.g. R3injury 99 days vs. R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts e.g. intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (e.g. hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR, R3injury, and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical ABMR were present in the population, and strategies that previously revealed antibody-mediated rejection (ABMR) in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.
2020-05-06 | GSE145780 | GEO
Project description:Acute cellular rejection occurs frequently during the first few weeks following liver transplantation. During this period its molecular phenotype is confounded by pro-inflammatory events elicited by surgery, ischemia-reperfusion injury and early post-transplant complications. To unambiguously define the molecular profile associated with rejection we collected sequential biological specimens from liver transplant patients at least 3 years after transplantation who developed rejection while enrolled in trials of intentional immunosuppression withdrawal
2016-06-01 | GSE70305 | GEO
Project description:Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant (HT) recipients during and following histologically-diagnosed rejection. Across 28 cell types, we identified significant differences in abundance in CD4+ and CD8+ T cells, fibroblasts, and endothelial cells across different biological classes of rejection (cellular, mixed, antibody-mediated). We observed a broad overlap in cellular transcriptional states across histologic rejection severity and biological class and significant heterogeneity within rejection severity grades that would qualify for immunomodulatory treatment. Individuals who had resolved rejection after therapy had a distinct transcriptomic profile relative to those with persistent rejection, including 216 genes across 6 cell types along pathways of inflammation, IL6-JAK-STAT3 signaling, IFNα/IFNγ response, and TNFα signaling. Spatial transcriptomics also identified genes linked to long-term prognostic outcomes post-HT. These results underscore importance of subtyping immunologic states during rejection to stratify immune-cardiac interactions following HT that are therapeutically relevant to short- and long-term rejection-related outcomes.
2025-03-05 | GSE290577 | GEO
Project description:We integrated three transplant rejection microarray studies examining gene expression in samples from pediatric renal, adult renal, and adult heart transplants. We performed one study ourselves and retrieved two others from the NCBI Gene Expression Omnibus (GEO)(GSE4470 and GSE1563). We identified 45 genes that were upregulated in common in acute rejection. Half were involved in one immune-related pathway. Among ten proteins we tested by serum ELISA, three successfully distinguished acute rejection from stable transplants. These were CXCL9, PECAM1, and CD44, with areas under the receiver operating characteristic curves of 0.844, 0.802, and 0.738, respectively. Immunohistochemistry showed that the PECAM1 protein was increased in acute rejection in renal, liver and heart transplants versus normal tissues. Our results show that integrating publicly-available gene expression data sets is a fast, powerful, and cost-effective way to identify serum-detectable diagnostic biomarkers. For new microarray experiments, we collected 18 acute rejection (AR) and 18 stable (STA) biopsy samples from pediatric renal allograft recipients at Stanford University. Written informed consent was obtained from all the subjects. The study was approved by the Stanford University Institutional Review Board. Nucleic acids from the samples were hybridized to Affymetrix U133 Plus 2.0 microarrays. AR samples were obtained at the time of a biopsy-proven acute rejection episode according to the Banff classification (IA, IIA, IIB). Prior to including the samples in this study, the diagnosis of acute rejection was confirmed by a pathologist. STA samples were obtained from patients with stable graft function during regular post-transplantation follow-up protocol biopsies. All three data sets (pediatric renal, adult renal, and adult heart) were normalized by the quantile-quantile method using dChip software. Ten proteins in serum were measured by using commercial ELISA kits.
2010-10-12 | E-GEOD-14328 | biostudies-arrayexpress
Project description:Major histocompatibility complex (MHC) genes of Rhodeus pseudosericeus
| PRJNA658822 | ENA
Project description:Major histocompatibility complex genotyping with massively parallel pyrosequencing
| PRJNA79667 | ENA