Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets and promotes chronic GVHD

ABSTRACT: Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single cell gene expression and T-cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While CNIs suppress the clonal expansion in CD8+ T-cells, alloreactive CD4+ T-cell clusters preferentially expanded during GVHD. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T-cell exhaustion but favored the differentiation to central memory T-cells. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T-cells with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to post-transplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that mediate cGVHD. Collectively, we show that although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific central memory T-cells, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T-cell clones.

ORGANISM(S): Mus musculus

PROVIDER: GSE255545 | GEO | 2024/04/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Peripheral blood T helper cells circulate with pathogenic tissue resident T helper cells in chronic GVHD

Project description:Chronic graft versus host disease (cGVHD) is a systemic autoimmune-like syndrome. The role of Tph cells in the pathogenesis of cGVHD has not been examined, although previous studies have shown that cGVHD is characterized by loss of Tfh cells. Here, we show that in cGVHD patients and in a murine model that reflects characteristic features of human cGVHD, the proportions of Tph cells among CD4+ T cells in the blood were expanded. These cells augmented memory B cell differentiation and production of IgG via IL-21. Adoptive transfer experiments showed recirculation between Tph in the blood and tissue-resident T helper (Trh) cells in GVHD target tissues. The TCR repertoires of blood Tph cells and Trh cells in GVHD target tissues of mice were highly overlapping.

2023-02-22 | GSE200520 | GEO

CSF1R inhibition promotes neuroinflammation and behavioural deficits during graft-versus-host disease in mice.

Project description:Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor MHC class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesised that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early post-transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients where CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signalling post-transplant failed to reverse GVHD-induced behavioural changes. Moreover, we observed aberrant behaviour in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.

2023-10-18 | GSE245360 | GEO

Tissue-Resident Memory T Cells in Human Kidney Transplants have alloreactive potential

Project description:The extent to which tissue-resident memory T (TRM) cells in transplanted organs possess alloreactivity is uncertain. This study investigates the alloreactive potential of TRM cells in kidney explants from four patients who experienced severe acute rejection leading to graft loss. Alloreactive T-cell receptors (TCRs) clones were identified in pre-transplant blood samples through mixed lymphocyte reactions, followed by single-cell RNA and TCR sequencing of the proliferated recipient T cells. Subsequently, these TCR clones were traced in the TRM cells of kidney explants, which were also subjected to single-cell RNA and TCR sequencing. The proportion of TRM cells expressing an alloreactive TCR in the four kidney explants varied from 0% to 9%. Notably, these alloreactive TCRs were predominantly found among CD4+ and CD8+ TRM cells with an effector phenotype. Intriguingly, alloreactive clones were present not only in recipient-derived TRM cells but also in donor-derived TRM cells, constituting up to 4% of the donor population, suggesting the presence of self-reactive TRM cells. Overall, our study demonstrates that T cells with alloreactive potential present in the peripheral blood prior to transplantation can infiltrate the kidney transplant and adopt a TRM phenotype.

2024-03-01 | GSE249197 | GEO

Glycolytic metabolism of pathogenic T cells enables early detection of GvHD by 13C-MRI.

Project description:Graft-versus-host disease (GvHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (HSCT). Definitive diagnosis of GvHD is invasive and biopsies of involved tissues pose a high risk of bleeding and infection. Our previous studies in a chronic GvHD mouse model demonstrated that alloreactive CD4+ T cells are distributed to target organs ahead of overt symptoms, meanwhile CD4+ T cell activation is tied to increased glycolysis. We aimed to compare the gene expression of allogeneic (mismatched) naive (Tn) and effector memory (Tem) CD4+ T cell subsets early post transplant. Specifically, we hypothesized that allogeneic CD4 effector memory T cells would show upregulated expression of genes related to glycolysis. We found that almost all enzymes of glycolysis were upregulated in effector memory CD4 T cells compared to naive cells, including transporters for glucose. In contrast, enzymes of the tricarboxylic acid cycle were not uniformly elevated.

2021-01-21 | GSE153591 | GEO

Glycolytic metabolism of pathogenic T cells enables early detection of GvHD by 13C-MRI

2021-01-21 | GSE147371 | GEO

Expression Profile of alloreactive CD8 and CD4 induced regulatory T cells

Project description:Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemic (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4 or CD8 T cells and tested their ability to suppress GVH and maintain GVL responses. We utilized major mismatched and haploidentical murine models of HCT with host-derived lymphoma or leukemia cell lines to evaluate GVH and GVL responses simultaneously. Alloreactive CD4 iTregs were effective in preventing GVHD, but abrogated the GVL effect against aggressive leukemia. Alloreactive CD8 iTregs moderately attenuated GVHD while sparing the GVL effect. Hence, we reasoned that using a combination of CD4 and CD8 iTregs could achieve the optimal goal of allo-HCT. Indeed, the combinational therapy was superior to CD4 or CD8 iTreg singular therapy in GVHD control; importantly, the combinational therapy maintained GVL responses. Cellular analysis uncovered potent suppression of both CD4 and CD8 effector T cells by the combinational therapy that resulted in effective prevention of GVHD, which could not be achieved by either singular therapy. Gene expression profiles revealed alloreactive CD8 iTregs possess elevated expression of multiple cytolytic molecules compared to CD4 iTregs, which likely contributes to GVL preservation. Our study uncovers unique differences between alloreactive CD4 and CD8 iTregs that can be harnessed to create an optimal iTreg therapy for GVHD prevention with maintained GVL responses.

2016-11-17 | GSE75118 | GEO

Somatic Gain-of-Function mTOR mutation in Clonally Expanded T-lymphocytes Associated with Chronic Graft-Versus-Host Disease

Project description:Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GVHD (cGVHD) carrying persistent CD4+ T cell clonal expansion which harbored somatic mTOR, NFKB2, and TLR2 mutations. Functional analysis of the discovered mTOR mutation indicated a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements supported increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggested mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest that somatic mutations may contribute to aberrant T cell proliferations and participate in the persistent immune activation in cGVHD paving the way for novel targeted therapies.

2020-04-12 | E-MTAB-8911 | biostudies-arrayexpress

Integrated Analysis of T-cell Repertoire and Transcriptome Shed Light into the Mechanisms of Regulatory T cell (Treg) Suppression of Acute Graft-versus-Host-Disease

Project description:CD4+ FOXP3+ regulatory T (Treg) cells are currently under clinical evaluation as an immunoregulatory cellular therapy for graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, we performed paired T cell receptor (TCR) sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT. We show that both Treg and Tcon underwent clonal expansion and that Treg did not interfere with the activation of alloreactive Tcon clones. Transcriptomic analysis revealed that Treg predominantly affected CD4 Tcon and to a lesser extent CD8 Tcon transcriptome, modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Treg did not interfere with the induction of gene sets involved in the GvT effect. Our results shed light into the mechanisms of acute GvHD suppression by Treg and will support the clinical translation of this immunoregulatory approach.

2022-07-15 | GSE205375 | GEO

Gene expression profile at single cell level of alloantigen-specific TEa CD4+ T cells after heart transplantation

Project description:Alloreactive CD4+ T cells play a central role in allograft rejection, We used single cell RNA sequencing (scRNA-seq) to analyze the cell states of alloreactive CD4+ T cells in periphery and allografts to better understand how alloreactive CD4+ T cells drive allograft rejection.

2023-09-28 | GSE221337 | 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.

2008-06-15 | E-GEOD-7510 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data