Gene expression profiling of skin and blood in human acute Graft-versus host disease (GVHD) of the skin
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PROVIDER: PRJNA989596 | ENA |
REPOSITORIES: ENA
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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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Project description:Single cell RNA-sequencing analysis of chronic graft-versus-host disease (GVHD) skin lesions
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Project description:Single cell RNA-sequencing analysis of acute graft-versus-host disease (GVHD) skin lesions
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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
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.
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Project description:The goal of the study is to understand the molecular mechanisms responsible for cutaneous GVHD.
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Project description:The goal of the study is to understand the molecular mechanisms responsible for cutaneous GVHD.
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Project description:Expression profiling of rat major histocompatibility complex and natural killer complex genes in skin explant assays reveals genes that are regulated in graft versus host disease. The major histocompatibility complex (MHC) is the most important genomic region that contributes to the genetic risk of graft rejection and graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Therefore, MHC matching is most essential for the success of clinical transplantations. However, the MHC contains in addition to MHC class I and class II genes that are genotyped for selection of donors further so far unidentified genes that also contribute significantly to the risk to develop acute GVHD. It is difficult to identify these MHC genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes that might be involved in the pathohysiology of GVHD by expression profiling. To reduce the complexity of our model, we used genetically well-defined inbred rat strains (PVG and BN) and skin explant assays, an in-vitro-model of graft versus host reaction (GVHR), to analyse the expression of MHC and natural killer complex (NKC) genes in a cutaneous GVHR by a custom microarray. A higher percentage of genes in these immunologically highly important genomic regions were regulated than in the rest of the genome. We observed a statistically significant regulation of 25 MHC and 6 NKC genes and 168 other genes (i.e., 4.9%, 14.0%, and 6.6%, respectively) in rat skin explants cultured in the presence of pre-stimulated allogeneic lymphocytes compared to control samples cultured in the presence of syngeneic lymphocytes. Seven MHC and 3 NKC genes were selected for analysis by quantitative real-time polymerase chain reaction PCR. Most of the results of the microarray were confirmed in the same experimental set that was used for the microarray analysis and in a second independent experimental set of skin explant samples. In addition, GVHD-affected skin lesions of transplanted rats were analysed and similar regulations of most of the selected MHC and NKC genes were observed. Thus, our skin explant model of GVHR is informative for the gene regulation during GVHD. Interestingly, the human homologues of several of the regulated genes are polymorphic and could therefore contribute to the genetic risk of GVHD. These genes include RT1-Dmb, C2, Aif1, Spr1, Ubd, and Olr1. The human homologues of these genes might be useful for risk assessment and diagnosis of GVHD in patients. Two-condition experiment, Stimulated vs. NonSimulated cells. 12 Biological replicates, 2 Technical Replicates (Dye Swap) per Biological Replicate.
2011-01-04 | E-GEOD-17928 | biostudies-arrayexpress
Project description:This phase II trial studies how well cyclophosphamide works in preventing chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant in patients with hematological malignancies. Giving chemotherapy and total-body irradiation before transplantation helps stop the growth of cancer cells and prevents the patient’s immune system from rejecting the donor’s stem cells. Healthy stem cells from a donor that are infused into the patient help the patient’s bone marrow make blood cells; red blood cells, white blood cells, and platelets. Sometimes, however, the transplanted donor cells can cause an immune response against the body’s normal cells, which is called graft-versus-host disease (GVHD). Giving cyclophosphamide after transplant may prevent this from happening or may make chronic GVHD less severe.
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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