Dataset Information

BLUEPRINT DNA methylation profiles of graft donors in allogenic hematopoietic stem cell transplantation

ABSTRACT: Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. We investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in HLA-matched sibling recipients prior to HSCT. We measured genome-wide DNA methylation levels in peripheral blood of 91 HSCT donors using Illumina Infinium HumanMethylation450 BeadChips. We showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We identified distinct DNA methylation marks in graft donors that are associated with aGVHD severity status in recipients. Together, our findings suggest that ‘epigenetic matching’ of HSCT donor-recipient pairs in a clinical setting may be used in conjunction with genetic matching to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome.

PROVIDER: EGAS00001001287 | EGA |

REPOSITORIES: EGA

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Publications

A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation.

Paul Dirk S DS Jones Allison A Sellar Rob S RS Mayor Neema P NP Feber Andrew A Webster Amy P AP Afonso Neuza N Sergeant Ruhena R Szydlo Richard M RM Apperley Jane F JF Widschwendter Martin M Mackinnon Stephen S Marsh Steven G E SG Madrigal J Alejandro JA Rakyan Vardhman K VK Peggs Karl S KS Beck Stephan S

Genome medicine 20151215

<h4>Background</h4>Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in ...[more]

PMID: 26669438

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Project description:Delayed graft function (DGF) is associated with a reduced long-term graft survival. Ischemia-reperfusion damage and donors' features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the role of recipients' characteristics in the development of DGF to discover early genomics biomarkers in peripheral blood mononuclear cells (PBMC) in order to identify patients at risk. We prospectively enrolled 932 kidney graft recipients from 466 donors for both kidneys. A total of 226 recipients experienced DGF. Among the 466 donors, 290 couples of recipients both patients presented with early graft function (EGF, group A), 50 couples experienced DGF (group B) and 126 couples of recipients were discordant as one presented DGF and the other promptly recovered graft function (group C). In group C we randomly selected 10 couples of DGF/EGF recipients. Peripheral blood mononuclear cells (PBMC) were harvested before transplantation; their transcriptomic profile was investigated by a microarray approach and microarray results were validated by qPCR in an independent group (DGF n=25; EGF n=25). In the whole study group, DGF was independently associated with both donors’ and recipient’s features. Moreover, group A, B and C presented significant differences in both donors’ and recipients’ characteristics. In group C of patients, DGF was significantly associated with body mass index, dialysis modality and number of mismatches. Two-hundred and seventy-three genes were differentially expressed before transplantation in discordant EGF/DGF patients of group C. Their main biological functions were immune dysfunction and inflammation. Among the differentially expressed genes, we observed a significant increase in the expression of CCR2, the MCP-1 receptor, in DGF patients. CCR-2 and MCP-1 up-regulation was confirmed in an independent cohort of patients. Our results suggest that recipients' clinical and immunological features, potentially modulated by dialysis modality, are associated with the development of DGF independently of donors' features.

Project description:The frequency of delayed function of kidney transplants varies greatly and is associated with the quality of graft, donor age, and the duration of cold ischemia time. Body weight differences between donor and recipient can affect primary graft function. The underlying mechanism is poorly understood. Here, we have transplanted kidney grafts from commensurate body weight (L-WD) or reduced body weight (H-WD) donor rats into syngeneic or allogeneic recipients. 24 hours post-transplantation, serum creatinine level in H-WD recipients was significantly higher compared to that of L-WD recipients indicating impaired primary graft function. We detected a 10 fold higher transcription of IL-6 and dramatically increased tubular destruction in grafts from H-WD recipients. This was accompanied by decreased expression of genes associated with kidney function and an up-regulation of other genes such as cytochrome P450 isoforms, FosL and Trib3 as revealed by DNA microarray analysis. A single application of IL-6 into L-WD recipients is sufficient to impair primary graft function and to cause tubular damage. Whereas, immediate neutralization of IL-6 receptor signaling rescued primary graft function resulting in low serum creatinine levels, well-preserved kidney graft architecture and a normalized gene expression profile. These findings have strong clinical implication as anti-IL6R treatment of patients receiving grafts from lower-weight donors could be used to improve primary graft function. The dataset comprises eight samples divided into four sample groups. Each group represents rat kidneys collected after allogeneic transplantation under a certain condition and includes two biological replicates. The first group is characterized by a high body weight difference between donor and recipient, rats in the second group exhibit a low weight difference. Group three and four are similar to group one, but underwent an additional treatment with anti-IL6R mAb or prednisolone immediately after transplantation.

Dataset Information

BLUEPRINT DNA methylation profiles of graft donors in allogenic hematopoietic stem cell transplantation

Publications

A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation.

Similar Datasets

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