Dysfunction of infiltrating cytotoxic CD8+ T cells within the graft promotes murine kidney allotransplant tolerance
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ABSTRACT:
PROVIDER: PRJNA1060247 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27405500_1.fastq.gz | Fastqsanger.gz | |||
| SRR27405500_2.fastq.gz | Fastqsanger.gz | |||
| SRR27405501_1.fastq.gz | Fastqsanger.gz | |||
| SRR27405501_2.fastq.gz | Fastqsanger.gz | |||
| SRR27405502_1.fastq.gz | Fastqsanger.gz |
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Project description:Tolerance of mouse kidney allografts arises in grafts that develop regulatory Tertiary Lymphoid Organs (rTLOs). scRNAseq data and adoptive transfer of alloreactive T cells post-transplant showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype. Establishment of rTLOs was required since adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite intragraft CD8+ cells with a regulatory phenotype, they were not essential for the induction and maintenance of kidney allograft tolerance. Analysis of scRNAseq data from allograft kidneys and malignant tumors identified similar regulatory-like cell types within the T cell clusters. Induction of cytotoxic CD8+ T cell dysfunction of infiltrating cells appears to be a beneficial mechanistic pathway that protects the kidney allotransplant from rejection through a process we call “defensive tolerance.” This pathway has implications for our understanding of allotransplant tolerance and tumor resistance to host immunity.
2024-06-20 | GSE252337 | GEO
Project description:Tolerance of mouse kidney allografts arises in grafts that develop regulatory tertiary lymphoid organs (rTLOs). Single-cell RNA-seq (scRNA-seq) data and adoptive transfer of alloreactive T cells after transplantation showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-γ. Establishment of rTLOs was required because adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite the presence of intragraft CD8+ cells with a regulatory phenotype, they were not essential for the induction and maintenance of kidney allograft tolerance since renal allotransplantation into CD8-KO recipients resulted in acceptance and not rejection. Analysis of scRNA-seq data from allograft kidneys and malignant tumors identified similar regulatory-like cell types within the T cell clusters and trajectory analysis showed that cytotoxic CD8+ T cells are reprogrammed into an exhausted/regulatory-like phenotype intratumorally. Induction of cytotoxic CD8+ T cell dysfunction of infiltrating cells appears to be a beneficial mechanistic pathway that protects the kidney allotransplant from rejection through a process we call "defensive tolerance." This pathway has implications for our understanding of allotransplant tolerance and tumor resistance to host immunity.
| S-EPMC11324304 | biostudies-literature
Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study Matched case-control observational study: 10 primary graft dysfunction cases vs 16 Good outcome cases. One replicate per array.
2008-09-15 | E-GEOD-9102 | biostudies-arrayexpress
Project description:This is an RNA-seq study of human lung transplant recipients. Bronchoalveolar lavage cells were collected on the first day after lung transplant. We performed bulk RNA-sequencing on 19 lung transplant recipients with severe primary graft dysfunction (PGD) and 19 lung transplant recipients without primary graft dysfunction. As this data is human identifiable, raw data are not included in this record.
2023-02-15 | E-MTAB-12282 | biostudies-arrayexpress
Project description:Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Recent data demonstrate that non-self recognition by graft infiltrating macrophages initiates transplant rejection. Using an experimental transplantation mouse model, we isolated graft-infiltrating macrophages from two transplantation settings: untreated rejecting mice and treated with mTORi-HDL nanobiologics. We used microarrays to detail the global programme of gene expression underlying macrophage dependent organ transplant rejection and identified distinct classes of up-regulated genes during this process, which are down-regulated following tolerogenic treatment with mTORi-HDL nanobiologics.
2018-10-31 | GSE119370 | GEO
Project description:BACKGROUND: Hypovolemia is common in lung donors before or after brain death. However, its impact on primary graft function (PGD) remains obscure. METHODS: A clinically relevant two-hit model of PGD was established by integrating hypovolemic shock (HS) and cold ischemia-reperfusion in a mouse model of orthotopic lung transplantation (LTx) from C57BL/6 to Balb/c. At -48 hours, HS was induced to donor by withdrawal of blood from femoral artery and keeping the mean arterial pressure at 15±5 mmHg for 4 h. At -24 hours, donor lungs were retrieved from mice with or without HS and stored at 0ºC until transplantation. CD11b-DTR mice were used as donor and treated with Diphtheria Toxin (DT) to deplete graft-infiltrating macrophages. RESULTS: HS mainly caused macrophage-predominant infiltration around pulmonary artery injury systemic inflammatory response, but little impairment of lung function even if in combination with cold ischemia-reperfusion. Transcriptional profiling showed HS pretreatment increased pulmonary damage and alveolar remodeling but ameliorated inflammatory infiltration when compared to one-hit model of 12 hours cold ischemia-reperfusion injury. The allografts with donor DT-treatment one day ahead of HS showed injury and dysfunction at donation and worsened further at 24 hours reperfusion, whereas the allografts with recipient DT-treatment immediately after transplantation showed similar function and histology to the control treated with saline. CONCLUSION: Donor hypovolemia causes pulmonary artery injury and infiltration but has little impact on allograft function, even in combination with 24 h cold ischemia. Graft-infiltrating macrophages are critical in protecting graft from HS-induced injury and cold ischemia-reperfusion injury.
2022-03-30 | GSE156322 | GEO
Project description:The significance of borderline changes (BL) in kidney allograft biopsies is widely debated. We examined differences in gene expression patterns between early clinical biopsy tissue and 3-month protocol biopsy tissue, all of which had histological BL changes and identified specific molecular BL patterns associated with poor graft outcome. The expression profiles were analyzed in training set of patients and next data were validated in validation cohort using RT-qPCR. Using the Illumina microarray technology, we observed greater expression of immunity- and inflammation-related genes in tissues from early clinical biopsies compared to 3-month protocol biopsies with BL findings. In tissues with early clinically manifested BL changes, graft deterioration within 24 months due to chronic rejection was associated with increased activation of immune, defense, and inflammatory processes, specifically with higher donor age and expression of macrophage receptor CLEC5A. In the 3-month protocol biopsies with BL changes, graft dysfunction was associated with increased expression of fibrinogen complex transcripts. This study highlights the molecular differences between clinical and subclinical biopsies with similar histological findings. The data also support a recommendation for frequent patient monitoring, especially in those who received grafts from expanded criteria donors (ECDs). The experiments were performed with total RNA derived from the renal graft biopsy samples of 28 different patients who had undergone a kidney transplantation. Only the patients with diagnosis of borderline changes early (M-bM-^IM-$2 months) or protocolar (3 months) were included in the study. RNA profiles of patients with stable and deteriorated graft function during 2 years after transplantation were compared. As microarray platform, Illumina HumanHT-12 v4.0 Expression BeadChips (Illumina) was used. The chip scanning was performed with a BeadStation 500 instrument (Illumina Inc), and the raw data were extracted with the BeadStudio Data Analysis Software (Illumina). The R software lumi package was used to further process the raw data. The quantile method was used for normalization.
2013-12-19 | E-GEOD-52694 | biostudies-arrayexpress
Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study
2008-09-15 | GSE9102 | GEO
Project description:Expression data from graft infiltrating macrophages treated with mTORi-HDL nanobiologics
| PRJNA488999 | ENA
Project description:Pre-existing lung restricted autoantibodies (LRA) are associated with a higher incidence of primary graft dysfunction (PGD) although it remains unclear whether LRA can drive its pathogenesis. In syngeneic murine left lung transplant recipients, pre-existing LRA worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor non-classical monocytes as well as host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecule was necessary for lung injury which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin proteins failed to rescue lung function. LRA- mediated injury was localized to the transplanted lung and dependent on IL1β-mediated permeabilization of pulmonary vascular endothelium which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL1R in the donor lungs prevented LRA-induced graft injury. In humans, pre-existing LRA was an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that pre-existing LRA can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.
2022-10-19 | GSE211501 | GEO