Donor Macrophages Modulate Rejection after Heart Transplantation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA852221 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19805700_1.fastq.gz | Fastqsanger.gz | |||
| SRR19805700_2.fastq.gz | Fastqsanger.gz | |||
| SRR19805701_1.fastq.gz | Fastqsanger.gz | |||
| SRR19805701_2.fastq.gz | Fastqsanger.gz | |||
| SRR19805702_1.fastq.gz | Fastqsanger.gz |
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Project description:Cellular rejection after heart transplantation imparts significant morbidity and mortality. Current immunosuppressive strategies are imperfect, target recipient T-cells, and have adverse effects. The innate immune response plays an essential role in the recruitment and activation of T-cells. Targeting the donor innate immune response would represent the earliest interventional opportunity within the immune response cascade. There is limited knowledge regarding donor immune cell types and functions in the setting of cardiac transplantation and no current therapeutics exist for targeting these cell populations. Distinct populations of donor and recipient macrophages co-exist within the transplanted heart. Donor CCR2+ macrophages are key mediators of allograft rejection and deletion of MYD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograft survival. This highlights the therapeutic potential of donor heart-based interventions.
2022-06-30 | GSE206801 | GEO
Project description:Acute rejection in cardiac transplant patients is still a contributing factor to limited survival of the implanted heart. Currently there are no biomarkers in clinical use that can predict, at the time of transplantation, the likelihood of post-transplantation acute rejection, which would be of great importance for personalizing immunosuppressive treatment. Within the Biomarkers in Transplantation initiative, the predictive biomarker discovery focused on data and samples collected before or during transplantation such as: clinical variables, genes and proteins from the recipient, and genes from the donor. Based on this study, the best predictive biomarker panel contains genes from the recipient whole blood and from donor endomyocardial tissue and has an estimated area under the curve of 0.90. This biomarker panel provides clinically relevant prediction power and may help personalize immunosuppressive treatment and frequency of rejection monitoring.
2017-09-29 | GSE33970 | GEO
Project description:Increased levels of donor-derived cell-free DNA (dd-cfDNA) in recipient plasma have been associated with acute cellular rejection (ACR) after heart transplantation. DNA sequence differences have been used to distinguish between donor and recipient cfDNA but epigenetic differences could also potentially identify dd-cfDNA. This study aimed to assess the feasibility of using ventricle-specific methylation patterns in human cfDNA as an alternative biomarker for ACR in cardiac transplantation.
2020-06-18 | GSE152648 | GEO
Project description:Chronic rejection after organ transplantation manifests as immunosuppressant-resistant graft vascular remodeling and fibrosis, which remains the dominant driver of mortality after the first year of heart transplantation. Single-cell RNAseq analysis of MHCII-mismatched heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating myeloid cells and regulatory T cells (Tregs). Using IL-33-deficient donor mice, it was revealed that graft fibroblast-derived IL-33 potently induced Amphiregulin (Areg) expression by recipient Treg. Areg is an epidermal growth factor secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessing recipient mice with Treg-specific deletion of Areg demonstrated that this pathway surprisingly contributes to chronic rejection. Specifically, heart transplants from recipients with Areg-deficient Tregs exhibited less vasculopathy and vessel-associated fibrotic niches infiltrated by recipient T cells. Mechanistically, we show that Areg does not impact Treg suppressive function, but that IL-33 mediated Treg-secretion of Areg increases fibroblast proliferation and migration. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Treg contributes to the progression of chronic rejection.
2024-12-02 | GSE235871 | GEO
Project description:BackgroundCellular rejection after heart transplantation imparts significant morbidity and mortality. Current immunosuppressive strategies are imperfect, target recipient T cells, and have adverse effects. The innate immune response plays an essential role in the recruitment and activation of T cells. Targeting the donor innate immune response would represent the earliest interventional opportunity within the immune response cascade. There is limited knowledge about donor immune cell types and functions in the setting of cardiac transplantation, and no current therapeutics exist for targeting these cell populations.MethodsUsing genetic lineage tracing, cell ablation, and conditional gene deletion, we examined donor mononuclear phagocyte diversity and macrophage function during acute cellular rejection of transplanted hearts in mice. We performed single-cell RNA sequencing on donor and recipient macrophages and monocytes at multiple time points after transplantation. On the basis of our imaging and single-cell RNA sequencing data, we evaluated the functional relevance of donor CCR2+ (C-C chemokine receptor 2) and CCR2- macrophages using selective cell ablation strategies in donor grafts before transplant. Last, we performed functional validation that donor macrophages signal through MYD88 (myeloid differentiation primary response protein 88) to facilitate cellular rejection.ResultsDonor macrophages persisted in the rejecting transplanted heart and coexisted with recipient monocyte-derived macrophages. Single-cell RNA sequencing identified donor CCR2+ and CCR2- macrophage populations and revealed remarkable diversity among recipient monocytes, macrophages, and dendritic cells. Temporal analysis demonstrated that donor CCR2+ and CCR2- macrophages were transcriptionally distinct, underwent significant morphologic changes, and displayed unique activation signatures after transplantation. Although selective depletion of donor CCR2- macrophages reduced allograft survival, depletion of donor CCR2+ macrophages prolonged allograft survival. Pathway analysis revealed that donor CCR2+ macrophages are activated through MYD88/nuclear factor kappa light chain enhancer of activated B cells signaling. Deletion of MYD88 in donor macrophages resulted in reduced antigen-presenting cell recruitment, reduced ability of antigen-presenting cells to present antigen to T cells, decreased emergence of allograft-reactive T cells, and extended allograft survival.ConclusionsDistinct populations of donor and recipient macrophages coexist within the transplanted heart. Donor CCR2+ macrophages are key mediators of allograft rejection, and deletion of MYD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograft survival. This highlights the therapeutic potential of donor heart-based interventions.
| S-EPMC9398940 | biostudies-literature
Project description:PBMC samples from heart transplant patients were profiled. Sample classification was based on endomyocardial biopsy at the time of sample collection. Keywords = Transplant Keywords = Transplantation Keywords = Heart Transplant Keywords = Graft Rejection Keywords = Rejection Keywords = PBMC Keywords = Immune Response Keywords = Peripheral Blood
2010-06-10 | E-GEOD-2445 | biostudies-arrayexpress
Project description:PBMC samples from heart transplant patients were profiled. Sample classification was based on endomyocardial biopsy at the time of sample collection. Keywords = Transplant Keywords = Transplantation Keywords = Heart Transplant Keywords = Graft Rejection Keywords = Rejection Keywords = PBMC Keywords = Immune Response Keywords = Peripheral Blood Keywords: other
2005-09-01 | GSE2445 | GEO
Project description:Antibody-mediated rejection, caused by antibodies against the donor human leukocyte antigen (HLA) molecules plays a fundamental role in graft rejection in transplantation. Most significant is transplant patients who generate antibodies against the donor HLA-DQ have the highest risk of rejection. In this study, we investigated the role of indirect CD4 T cell epitopes in the formation of donor-specific antibodies (DSA). Using antigen mapping techniques in kidney and heart transplant recipients with HLA-DQ DSA, we identified two polymorphic hotspots in the HLA-DQ gene that generated alloreactive CD4 T cell responses. To study the functional significance of indirect CD4 T cells, we first mapped epitopes recognised by H2-Kb C57Bl6 mice against a skin graft from H2-Kd Balb/c mice. We identified a CD4 T cell epitope, specific for amino acids 287-301 derived from the H2-Kd protein, that generated tetramer-binding Kd287+ CD4 T cells during rejection. Importantly, the transfer of Kd287+ CD4 T cells into T cell-deficient mice was sufficient to drive an antibody response against the donor H2-Kd molecule. Lastly, we found that administration of systemic high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the formation of Kd287+ CD4 T cells and diminished DSA formation. Together, these findings demonstrate that the identification of donor antigens indicates the potential for inducing donor-specific immune tolerance in transplantation.
2024-09-17 | GSE277075 | GEO
Project description:Renal dendritic cells play key roles in renal homeostasis and during kidney allograft rejection. Microarray analysis aims to evaluate whether dendritic cells modulate their gene expression profile in relation to their distribution in the different renal compartments (with varying biophysical characteristics), under homeostatic conditions and during acute renal allograft rejection (3 days post-transplantation). Renal dendritic cells from homeostatic (healthy) kidneys and donor/host dendritic cells from renal allografts (3 days post-kidney transplantation) were isolated from cortex and medulla, through fluorescence-activated cell sorting (FACS). Total RNA was isolated from FACS-sorted cells and amplified. The cDNA product was fragmented, biotin-labeled and hybridized on Affimetrix arrays.
2015-02-04 | E-GEOD-65564 | biostudies-arrayexpress
Project description:Solid organ transplantation in the mouse is a powerful research tool that has provided a pathway to find important mechanistic insights into the regulation of allograft injury, allograft immunopathology, and transplant rejection/tolerance, and that has unique advantages over transplantation in larger species, due to the well characterization of mouse genome and availability of genetically modified animals. However, setup of mouse liver, heart and kidney transplantation is a technically demanding surgical procedure, especially the orthotopic liver transplantation in mouse. Here, we performed Microwell-based single cell RNA-seq of three mouse organ transplantation models (liver, heart and kidney). Comparison of lymphocytes, parenchyma cells and peripheral blood mononuclear cells in liver, heart and kidney revealed distinct immune microenvironment at acute rejection and tolerance state respectively. Single-cell transcriptome analysis of mouse allograft without immunosuppressive drugs provided rich resources to help understand functioning solid-organ transplantation in human.
2022-11-18 | GSE189069 | GEO