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Corticosteroid resistance is predetermined by early immune response dynamics at acute Graft-versus-Host disease onset

ABSTRACT: Transcriptomic analysis from patient's samples after hematopoietic stem cell transplantation with or without acute GVHD

ORGANISM(S): Homo sapiens

PROVIDER: GSE229733 | GEO | 2025/01/01

REPOSITORIES: GEO

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Acute graft-versus-host disease (gene expression profiling)

Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for high-risk hematological malignancies, yet a major complication associated with this therapy is acute graft-versus-host disease (GVHD). Despite a well-defined pathophysiological mechanism, there are no definitive markers for predicting acute GVHD development or progression to advanced stages. In the current study, we enrolled four acute GVHD and four acute GVHD-free recipients of allogeneic HSCT and collected peripheral blood just prior to onset of clinical acute GVHD for analysis on Affymetrix GeneChip Human Genome U133 Plus 2.0 microarrays. We noted significant differences in expression of 1,658 genes between control and acute GVHD patients, based on an analysis of covariance (ANCOVA) by type of transplant, a pooled error estimate, and a false discovery rate (FDR) of 10%. In conclusion, we offer the first report of a preliminary molecular signature of acute GVHD in allogeneic HSCT patients.

2008-04-09 | GSE7510 | GEO

ROCK1 inhibition reduces steroid-refractory acute graft-versus-host disease

Project description:To identify kinases in immune cells of patients with SR-GVHD we isolated leukocytes and specifically enriched kinases via kinet-beads-technology. Rho Kinase Type 1 (ROCK1) was identified as the most abundant kinase in SR-GVHD.

2023-12-19 | PXD012036 | Pride

Gene expression profiling of skin and blood in human acute Graft-versus host disease (GVHD) of the skin

Project description:GVHD following allogneeic hematopoietic stem cell transplantation is described as a T cell mediated disease. We analyze mononuclear phagocyte subsets and other leukocyte populations in blood and skin from patients with acyte cutaneous GVHD

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Prediction of graft-versus-host disease in humans by donor gene expression profiling

Project description:Graft-versus-host disease (GVHD) results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantion (AHCT). Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be “stronger alloresponders” than others, and consequently more likely to elicit GVHD. To this end, we analyzed the gene expression profile of CD4 and CD8 T cells from 50 AHCT donors. We found that pre-AHCT gene expression profiling segregates donors whose recipient suffered from GVHD or not. The “dangerous donor” trait (GVHD+ recipient) is under polygenic control and is shaped by the activity of genes that regulate diverse cell functions including TGF-β signaling and cell proliferation. We also performed gene expression profiling in T cells harvested from 40 AHCT recipients on day 365 post-AHCT. The donor gene profile defined on day 0 showed exceedingly strong correlation with that of recipient CD4 and CD8 T cells harvested one year post-AHCT. These data suggest that donor gene profiles linked with GVHD were largely imprinted at the hematopoietic stem cell level. The ability to discriminate strong and weak alloresponders using gene expression profiling could pave the way to personalized transplantation medicine. Keywords: comparative gene profile, cell type comparaison, GVHD+, GVHD-

2007-03-27 | GSE4624 | GEO

Donor T cells in ovarian graft versus host disease

Project description:Analysis of donor CD4+ and CD8+ T cells purified from spleens and ovaries after murine syngeneic and allogeneic hematopoietic stem cell transplantation Infertility associated with ovarian failure is a serious late complication for female survivors of allogeneic hematopoietic stem cell transplantation (SCT). While the role of pretransplant conditioning regimen has been well appreciated, increasing application of reduced-intensity conditioning facilitated us to revisit the other factors possibly affecting ovarian function after allogeneic SCT. We have addressed whether donor T-cell mediated graft-versus-host disease (GVHD) could be causally related to female infertility in mice. To study transcriptomes of donor T cells infiltrating into the ovary, donor T cells were sorted from recipients' ovaries and microarray analysis was performed.

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6-phosphogluconate dehydrogenase blockade in T Cells mitigates acute graft-versus-host disease while preserving graft-versus-tumor activity

Project description:T cells undergo significant metabolic reprogramming after allogeneic hematopoietic cell transplantation (allo-HCT). However, the influence of metabolic pathway reprogramming on altering the severity and mortality of acute graft-versus-host disease (aGvHD), a critical allo-HCT complication, remains unclear. Through single-cell RNA sequencing (scRNA-seq) of allogeneic T cells isolated from the spleen of GvHD mice, we uncovered that 6-phosphogluconate dehydrogenase (6PGD), the second major rate-limiting enzyme in the oxidative pentose phosphate pathway, is upregulated and activated during allo-HCT. Clinical and histopathological analyses revealed that 6PGD deficiency in donor T cells significantly mitigates aGvHD severity and mortality in murine models of acute GvHD. An in vitro assay using murine and human T cells and an in vivo murine GvHD model showed that in the absence of an intact 6PGD pathway, donor T cell proliferation was reduced. Metabolic analyses confirmed that blocking 6PGD activity shifted T cell metabolism from glycolysis to oxidative phosphorylation (OXPHOS), as evidenced by isotope-labeled metabolic tracing and Seahorse assays. Pharmacological inhibition of 6PGD with 6-aminonicotinamide (6AN) demonstrated similar efficacy as the infusion of donor 6PGD deficient T cells in reducing aGvHD severity in allogeneic aGvHD and humanized xenogeneic GvHD models. Importantly, 6PGD inhibition preserved the graft-versus-tumor (GvT) effect by promoting the generation of a small subset of effector T cells with potent anti-tumor activity. From these findings we propose 6PGD as a promising therapeutic target for alleviating aGVHD the beneficial GvT effects.

2025-04-30 | GSE289995 | GEO

FK506 and Lactobacillus acidophilus Ameliorate Acute Graft-Versus-Host Disease by Modulating the T Helper 17/Regulatory T-Cell Balance

Project description:Graft-versus-host disease (GvHD) is critical complication after allogeneic hematopoietic stem cell transplantation (HSCT). The immunosuppressants given to patients undergoing allogeneic HSCT disturb the microbiome and the host immune system, potentially leading to dysbiosis and inflammation. The intestinal microbiome is a target for the development of novel therapies for GvHD. We determined the effect of the combination of tacrolimus (FK506) and Lactobacillus acidophilus on GvHD.

2021-05-11 | GSE174214 | GEO

Transcriptome analysis of acute graft-versus-host disease in children

Project description:Steroid-refractory gastrointestinal graft-versus-host disease (GI GVHD) is a major barrier to successful hematopoietic stem cell transplant (HSCT). Poor understanding of the pathophysiology of GI GVHD contributes to continued poor outcomes and high mortality rates. We therefore obtained rectosigmoidal mucosal biopsies from post-HSCT patients with GI GVHD and submitted them to RNA-sequencing in order to transcriptomally characterize GI GVHD. These were compared to patients undergoing endoscopy for routine clinical indications. Using single end, 50bp reads processed using Kallisto using genome annotations from Gencode v24 with transcripts per million as the output. We included 14,239 trancsripts in our analysis, where we compared GVHD vs non-GVHD with significance defined as FDR<0.05 and FC 1.5 using R package DESeq2. We identified 164 key genes, of which 141 were upregulated in GVHD, and were ontologically related to microbial response, key immune effectors, and cell migration/chemotaxis. Down-regulated genes were related to nutrient metabolism. Additionally, we performed WGCNA that highlighted ERK as a key upregulated pathway in GI GVHD.

2022-03-07 | GSE168116 | GEO

Effect of hBD-2 treatment on gene expression in the colon of acute graft-versus-host disease (GVHD) mice

Project description:Wildtype (WT) BALB/c mice were treated with allogeneic hematopoietic cell transplantation (allo-HCT) in order to induce acute GVHD. C57BL/6 mice were used bone marrow (BM) and T cell donor mice. We studied the effect of oral hBD-2 treatment versus vehicle (PBS) control treatment on the gene expression in the colon, as main GVHD target organ.

2022-12-23 | GSE190796 | GEO

Expression profiling in exosomal miRNAs of patients with late-onset acute graft-versus-host disease in Allogeneic Hematopoietic Stem Cell Transplantation

Project description:Recent studies have demonstrated exosomal microRNAs are potential in facilitating molecular diagnosis. Currently, little is known about the underlying mechanism of late-onset acute GVHD (LA GVHD). Identification of altered differential expression profiling of miRNAs in exosome will be useful for understanding role of miRNA in the LA GVHD. The purpose of this study is to investigate the relevance of miRNAs in exosome derived from patients developing LA GVHD after allogeneic HSCT.

2018-07-08 | GSE110435 | GEO

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