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Comparative analysis of skin- and gut-homing CD8+ T cells in aHSCT patients developing acute graft versus host disease (aGvHD)

ABSTRACT: Patients diagnosed with cutaneous and/or gastrointestinal aGvHD provide a unique opportunity to perform an in-depth comparison of activated human CD8+ T cells homing to the gut and skin, in some cases even within the same host, at the same time, acting as key players in the same human disease, and exerting their effector functions in these two tissue environments. This study aims at the identification of novel biomarkers associated with skin- and gut-homing CD8+ T cells in general, and CD8+ T cell markers possibly linked to CTL-mediated skin- and gut damage in aGvHD in particular.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103569 | GEO | 2018/11/01

REPOSITORIES: GEO

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IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice II

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IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-versus-host disease in mice I

Project description:CD4+ and CD8+ T cells can reciprocally differentiate into Th/Tc1, Th/Tc17 and Th/Tc22. Although alloreactive Th/Tc1 cells play a critical role in initiating pathogenesis of gut acute graft-versus-host disease (Gut-aGVHD), the pathogenic T cells in steroid-resistant Gut-aGVHD (SR-Gut-aGVHD) remains unclear. Here, we show that in murine models of SR-Gut-aGVHD, the pathogenesis is associated with reduction of IFN-g+ Th/Tc1 and IL-17A+IL-22- Th/Tc17 but expansion of IL-17-IL-22+ Th/Tc22, particularly Tc22 cells. IL-22 from Th/Tc22 cells causes dysbiosis. Using a Gut-aGVHD model induced by alloreactive IFN-g-/- CD8+ T cells, we show that the Gut-aGVHD pathogenesis requires both dysbiosis and depletion of CX3CR1hi mononuclear phagocytes (MNP) that regulate intestinal bacterial translocation. Absence of IFN-g leads to preferential expansion of Tc22 that induce dysbiosis by augmenting RegIIIg production, and depletion of CX3CR1hi MNP via its PD-1 interaction with tissue PD-L1. Interestingly, SR-Gut-aGVHD is also associated with depletion of CX3CR1hi MNP that reduces expansion of Tc22 under steroid treatment. Our studies indicate that expansion of Th/Tc22, dysbiosis, and depletion of CX3CR1hi MNP cells play critical roles in SR-Gut-aGVHD pathogenesis. These results provide new avenue towards studies in patients and call for caution in clinical testing of IL-22 agonists or IFN-g antagonist in patients.

2020-12-27 | GSE159031 | GEO

Transcription profiling of human leukocytes from peripheral blood stem cell transplant patients to investigate acute graft versus host disease aGVHD

Project description:Allogeneic peripheral blood stem cell transplantation (PBSCT) is indicated for the treatment of high-risk hematological malignancies, and in some cases is a cancer cure. A major complication associated with PBSCT (affecting approximately half of recipients) is acute graft-versus-host disease (aGVHD). In aGVHD, alloreactive donor T cells becoming activated by host dendritic cells (DC) in response to pro-inflammatory cytokines released during the conditioning regimen. The result is donor-derived CD4+ T helper-type 1 (Th1) cells maturing and subsequently imposing cytolytic effector responses on host tissues, resulting in multi-organ damage. Despite this well-defined pathophysiological mechanism, there are no definitive markers for predicting aGVHD development or progression to clinically advanced stages. In the current study, we enrolled 8 PBSCT recipients in an IRB-approved study and collected peripheral blood at the time to engraftment. Of these, four patients developed aGVHD within 5-10 days post transplant. The remaining four patients were aGVHD-free. Using total RNA collected from whole blood leukocytes, we analyzed each recipientâs gene expression profile on Affymetrix GeneChip Human Genome U133 Plus 2.0 microarrays. Experiment Overall Design: Samples 1-4 are control patients; 5-8 are aGVHD patients. Peripheral blood was collected at engraftment and used for microarray analysis. In analysing the data, the type of transplant (MUD, related) was used as a covariate to assess if there were significant changes in gene expression between the control (1-4) and aGVHD (5-8) groups, based on a 10% FDR with a pooled error estimate.

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Plasma in patients with acute myeloid leukemia (AML) with acute graft versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation vs Plasma in patients with AML without aGVHD

Project description:Comparing between plasma cytokine proteins on AML patients with or without aGVHD Comparing between plasma cytokine proteins on AML patients with or without aGVHD after allogeneic hematopoietic stem cell transplantation, Day+14

2022-06-11 | GSE205842 | GEO

Distinctive Transcriptional and Microbial Signature in Cutaneous Acute Graft-vs-Host-Disease

Project description:Skin acute graft-vs-host disease (aGVHD) is often the first manifestation of GVHD, yet very few preclinical and clinical studies have focused on this target organ, leaving a critical information gap in the pathophysiology of GVHD. We hypothesized that analysis of host gene expression and microbiome profiling could yield novel insights into the molecular and immunologic mechanisms underlying skin GVHD. Our objectives were to determine the differential host gene expression and microbiome profile of human skin aGVHD samples compared to normal skin, and aGVHD corticosteroid responders to non-responders. We performed RNA-Sequencing on lower arm biopsies from 45 patients compared to 10 healthy controls. Our findings suggest a distinctive transcriptional signature of cutaneous aGVHD, that could identify potentially actionable targets for prevention or treatment of corticosteroid refractory disease. Our analysis suggests a key role of dendritic cells and macrophages, potentially mediated by differential expression of MIF, in the development of cutaneous aGVHD and corticosteroid responsiveness. Additionally, we describe a unique microbial signature in cutaneous aGVHD that includes skin microbes not previously described in this population.

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Transcriptional profiling of PBMC from patients with aGvHD and patients without aGvHD after alloHSCT

Project description:The goal of this study are to identify critical biomarkers distinguishing alloHSCT recipients with aGvHD from alloHSCT recipients without aGvHD in two separate cohorts. Total RNA was isolated from the peripheral blood mononucleated cells and then quantified on a Bioanalyzer. Whole transcriptome sequencing libraries (3 pairs of aGvHD and controls, 6 libraries in total) were prepared following the manufacturer’s instructions for the Whole Transcriptome Sample Prep Kit (Illumina) by GENEWIZ Company. 1148 presented significant alterations in cases with aGvHD (t test, FDR corrected P < 0.05, |fold change|>1.5). Transcriptomic pathway analysis showed that the GPL metabolism pathway was one of the most significant pathways with Bonferroni correction P value (Q value) less than 0.001, indicating that it was a critical pathway related to the development of aGvHD.

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HIV-1 selectively targets gut-homing CCR6+CD4+ T-cells via mTOR-dependent mechanisms.

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Project description:We report the application of next generation sequencing technology for high-throughput transcriptom profiling of mucosal associated invariant T (MAIT) cells from patients with or without acute graft versus host disease (aGVHD) post allogenetic hematopoietic stem cell transplantation, and the healthy subjects as the contorls. Totally, MAIT cells from 4 patients with aGVHD, 3 patients without aGVHD and 3 healthy controls were detected in this study. Gene Set Enrichment Analysis (GSEA) on the sequencing data show the enrichments of interferon alpha response pathway in recipients with aGVHD and recipients without aGVHD, in comparison with healthy controls. Enrichment of primary immunodeficiency gene set is found in recipients without aGVHD when compared with aGVHD patients and healthy controls. This study provides some preliminary investigation to the mechanical mechanism of MAIT cells in the aGVHD development.

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A clinical trial of Vedolizumab vs. placebo (dummy drug) for the prevention of intestinal Acute Graft Versus Host Disease (aGvHD), in patients undergoing allo-HSCT for a hematologic malignancy, (cancers that affect the blood and/or lymphatic system).

Project description:Main Objective: To evaluate the efficacy of vedolizumab when added to background aGvHD prophylaxis regimen compared to placebo and background aGvHD prophylaxis regimen on intestinal aGvHD-free survival by Day +180 in subjects who receive allo-HSCT as treatment for a hematologic malignancy or myeloproliferative disorder. Primary end point(s): The primary endpoint is intestinal aGvHD-free survival by Day +180 after allo HSCT. Intestinal aGvHD is defined as Stage 1-4 intestinal involvement per Acute Graft versus-Host Disease Clinical Stage criteria.

| 2554383 | ecrin-mdr-crc

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