Spatial transcriptomics reveals distinct role of monocytes/macrophages with high FCGR3A expression in kidney transplant rejections
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PROVIDER: PRJNA1302304 | ENA |
REPOSITORIES: ENA
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Project description:Kidney transplant rejections are classified as active antibody mediated rejection (AMR) and cell mediated rejection (TCMR), with AMR primarily driven by antibodies produced by B cells, whereas TCMR is mediated by T lymphocytes that orchestrate cellular immune responses against the graft. Emerging evidence highlights the essential roles of innate immune cells in rejections, especially monocytes/macrophages and natural killer (NK) cells. However, the roles of specific innate immune cell subpopulations in kidney allograft rejection remain incompletely understood. Exploiting the spatial transcriptomics and formalin-fixed paraffin-embedded (FFPE) core needle biopsies from human kidney allografts, we demonstrated that non-rejection, AMR, acute TCMR and chronic active AMR have distinct transcriptomic features. Subclusters of monocytes/macrophages with high Fc gamma receptor IIIA (FCGR3A) expression were identified in C4d-positive active AMR and acute TCMR, and the spatial distribution of these cells corresponded to the characteristic histopathological features. Key markers related to monocyte/macrophage activation and innate alloantigen recognition were upregulated, along with metabolic pathways associated with trained immunity in AMR and TCMR. Taking together, these findings revealed that intragraft monocytes/macrophages with high FCGR3A expression play a critical role in kidney transplant rejections.
2025-09-09 | GSE304669 | GEO
Project description:In this proof-of-concept study, spatial transcriptomics combined with public single-cell RNA sequencing data were used to explore the potential of this technology to study kidney allograft rejection. We aimed to map gene expression patterns within diverse pathological states by examining biopsies classified across non-rejection, T cell-mediated acute rejection, and interstitial fibrosis and tubular atrophy (IFTA). Our results revealed distinct immune cell signatures, including those of T and B lymphocytes, monocytes, mast cells, and plasma cells, and their spatial organization within the renal interstitium. We also mapped chemokine receptors and ligands to study immune-cell migration and recruitment. Finally, our analysis demonstrated differential spatial enrichment of transcription signatures associated with kidney allograft rejection across various biopsy regions. Interstitium regions displayed higher enrichment scores for rejection-associated gene expression patterns than did tubular areas, which had negative scores. This implies that these signatures are primarily driven by processes unfolding in the renal interstitium. Overall, this study highlights the value of spatial transcriptomics for revealing cellular heterogeneity and immune signatures in renal transplant biopsies, and demonstrates its potential for studying the molecular and cellular mechanisms associated with rejection. However, certain limitations must be borne in mind regarding the development and future applications of this technology.
2024-05-02 | GSE245870 | GEO
Project description:We used a murine kidney transplantation model and single-cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques including machine learning, we demonstrated that kidney allograft-infiltrating myeloid cells followed a trajectory of differentiating from monocytes to pro-inflammatory macrophages, and exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was Axl, a member of the receptor tyrosine kinase familyTAM(Tyro3/Axl/Mertk).
2020-09-02 | GSE157292 | GEO
Project description:Transcriptomics of Kidney Transplant Recipients after Cytomegalovirus DNAemia
| PRJNA708352 | ENA
Project description:Tacrolimus (Tac) is an effective anti-rejection agent in kidney transplantation, but its off-target effects make withdrawal desirable. While studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs. unsuccessful Tac removal are unknown. We performed microarray analyses of PBMC RNA from subjects enrolled in the Clinical Trials in Organ Transplantation-09 study in which stable kidney transplant recipients were randomized to Tac withdrawal or maintenance of standard immunosuppression beginning 6-mo post-transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a distinct, T cell-specific, downregulatory, and pro-apoptotic gene program. Functional analyses suggested stronger donor-reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data suggest that successful Tac withdrawal can unleash an active, protective pro-apoptotic T cell program, and provide the foundation for developing strategies to promote this protective immunological phenotype in kidney transplant recipients.
2020-02-18 | GSE145408 | GEO
Project description:Background: Hepatitis E Virus (HEV) is a new causative agent of chronic hepatitis in solid organ transplant recipients in Europe. Factors associated with the occurrence and persistence of chronic HEV infection remain largely unknown but chronic evolution seems to be the consequence of hostM-bM-^@M-^Ys immunological factors rather than of viral factors. Method: In a prospective case-control study, we have determined in whole blood of chronically HEV-infected kidney-transplant recipients the host response using microarray technology. Results: Chronically HEV-infected kidney-transplant recipients exhibited a specific transcriptional program, in which interferon effectors were prominent. The intensity of expression of each signatureM-bM-^@M-^Ys gene was significantly lower in patients who were subsequently cleared of HEV than in patients who were not. Furthermore, in patients who were cleared of HEV, a higher expression of these genes was associated with a longer delay until HEV clearance. Conclusions: The specific transcriptional program determined in chronically HEV-infected kidney-transplant recipients suggests an activation of type I interferon response. Intensity of interferon-stimulated genes expression could be useful to forecast the outcome of infection. High expression of interferon-stimulated genes could signify a dysregulation in the interferon response that might favour the persistence of the HEV infection. TrialM-bM-^@M-^Ys registration number: NCT01090232; RegistryM-bM-^@M-^Ys URL: http://clinicaltrials.gov/ct2/show/study/NCT01090232?term=kidney+transplant+recipients&cntry1=EU%3AFR&rank=2 Total RNA was extracted from whole-blood sample or monocytes of kidney-transplant patients with or without chronic hepatitis E (CHE) infection. Control patients were matched up with CHE patients for age, sex, time since kidney transplant and immunosuppressive treatment.
2013-01-29 | E-GEOD-36539 | biostudies-arrayexpress
Project description:In the present work, we have used whole genome expression profiling of peripheral blood samples from 51 patients with biopsy-proven acute kidney transplant rejection and 24 patients with excellent function and biopsy-proven normal transplant histology. The results demonstrate that there are 1738 probesets on the Affymetrix HG-U133 Plus 2.0 GeneChip representing 1472 unique genes which are differentially expressed in the peripheral blood during an acute kidney transplant rejection. By ranking these results we have identified minimal sets of 50 to 150 probesets with predictive classification accuracies for AR of greater than 90% established with several different prediction tools including DLDA and PAM. We have demonstrated that a subset of peripheral blood gene expression signatures can also diagnose four different subtypes of AR (Banff Borderline, IA, IB and IIA) and the top 100 ranked classifiers have greater than 89% predictive accuracy. Finally, we have demonstrated that there are gene signatures for early and late AR defined as less than or greater than one year post-transplant with greater than 86% predictive accuracies. We also confirmed that there are 439 time-independent gene classifiers for AR. Based on these results, we conclude that peripheral blood gene expression profiling can be used to diagnose AR at any time in the first 5 years post-transplant in the setting of acute kidney transplant dysfunction not caused by BK nephropathy, other infections, drug-induced nephrotoxicity or ureteral obstruction. Keywords: kidney transplantation, peripheral blood, DNA microarrays, acute kidney rejection, biomarkers Microarray profiles of peripheral blood from 51 biopsy-proven acute kidney rejection (AR) and 24 well-functioning kidney transplants were randomized and compared using class comparisons, network and biological function analyses.
2014-03-01 | E-GEOD-15296 | biostudies-arrayexpress
Project description:Diabetes mellitus (DM) after transplantation remains a crucial clinical problem in kidney transplantation. To obtain insights into molecular mechanisms underlying the development of post-transplant diabetes mellitus (PTDM) and its early impact on glomerular structures, here we comparatively analyze the proteome of histologically normal appearing glomeruli from patients with PTDM from normoglycemic (NG) transplant recipients, and from recipients with pre-existing type 2 DM (PTDM)
2023-10-24 | PXD042188 | Pride
Project description:The post kidney transplant period is associated with insulin resistance partly due to corticosteroids. Patients on minimal corticosteroid therapy receiving tacrolimus (FK506) for immunosuppression also are affected. FK506 inhibits calcineurin in immune cells. Skeletal muscle calcineurin, which also might be inhibited, mediates exercise-induced transcription leading to more insulin-sensitive muscle. This study was performed to determine if gene transcription responses to exercise are lower in patients awaiting kidney transplant or 3 months post-transplant on a low-steroid, FK506 protocol.
2015-09-30 | GSE68585 | GEO