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Inhibition of Bromodomain and Extra Terminal (BET) domain activity modulates the IL-23R/IL17 axis and suppresses acute Graft-Versus-Host Disease [ChIP-seq]

ABSTRACT: Acute graft-versus-host disease (GVHD) is the major cause of non-relapse mortality post-allogeneic stem cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Treatment options for steroid-refractory acute GVHD are limited. Bromodomain and Extraterminal Domain (BET) inhibitors PLX51107 and PLX2853, deemed safe in human clinical trials in high risk malignancies, significantly downregulate pro-inflammatory Th1 and Th17 responses without impacting T regulatory cells, improving survival in murine models of acute GVHD while retaining beneficial graft-versus-leukemia effects. Modulation of the IL23/STAT3 axis via BET inhibition resulted in a reduction of pathogenic Th1/Th17 cells in the spleen and acute GVHD target organs such as the gastrointestinal tract. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183883 | GEO | 2021/09/12

REPOSITORIES: GEO

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Inhibition of Bromodomain and Extra Terminal (BET) domain activity modulates the IL-23R/IL17 axis and suppresses acute Graft-Versus-Host Disease [RNA-Seq]

Project description:Acute graft-versus-host disease (GVHD) is the major cause of non-relapse mortality post-allogeneic stem cell transplantation. The majority of patients non-responsive to front line treatment with steroids have an estimated overall 2-year survival rate of only 10%. Treatment options for steroid-refractory acute GVHD are limited. Bromodomain and Extraterminal Domain (BET) inhibitors PLX51107 and PLX2853, deemed safe in human clinical trials in high risk malignancies, significantly downregulate pro-inflammatory Th1 and Th17 responses without impacting T regulatory cells, improving survival in murine models of acute GVHD while retaining beneficial graft-versus-leukemia effects. Modulation of the IL23/STAT3 axis via BET inhibition resulted in a reduction of pathogenic Th1/Th17 cells in the spleen and acute GVHD target organs such as the gastrointestinal tract. Based on our preclinical data presented here, PLX51107 will enter clinical trial for refractory acute GVHD in a Phase 1 safety, biological efficacy trial.

2021-09-12 | GSE183884 | GEO

Tc17 cells are a pro-inflammatory, plastic lineage of pathogenic CD8+ T-cells that induce GVHD without anti-leukemic effects

Project description:IL-17-producing cells are important mediators of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT). Here we demonstrate that a distinct CD8+ Tc17 population develops rapidly after SCT but fails to maintain lineage fidelity such that they are unrecognizable in the absence of a fate reporter. Tc17 differentiation is dependent on alloantigen presentation by host-DC together with IL-6. Tc17 cells express high levels of multiple prototypic lineage-defining transcription factors (e.g. RORgt, T-bet) and cytokines (e.g. IL-17A, IL-22, IFNg, GM-CSF, IL-13). Targeted depletion of Tc17 early after transplant protects from lethal acute GVHD, however Tc17 cells are non-cytolytic and fail to mediate graft–versus–leukemia (GVL) effects. Thus, the Tc17 differentiation program during GVHD culminates in a highly plastic, hyper-inflammatory, poorly-cytolytic effector population which we term inflammatory Tc17 (iTc17). Since iTc17 mediate GVHD without contributing to GVL, therapeutic inhibition of iTc17 development in a clinical setting represents an attractive approach for separating GVHD and GVL. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2015-09-13 | E-GEOD-70931 | biostudies-arrayexpress

Genome-wide regulatory analysis reveals T-bet controls Th17 lineage differentiation through direct suppression of IRF4

Project description:The complex relationship between Th1 and Th17 cells is incompletely understood. The transcription factor T-bet is best known as the master regulator of Th1 lineage commitment. However, attention is now focused on the repression of alternate T cell subsets mediated by T-bet, particularly the Th17 lineage. Specifically it has recently been suggested that pathogenic Th17 cells express T-bet and are dependent on IL-23. However, T-bet has previously been shown to be a negative regulator of Th17 cells. We have taken an unbiased approach to determine the functional impact of T-bet on Th17 lineage commitment. Genome-wide analysis of functional T-bet binding sites provides an improved understanding of the transcriptional regulation mediated by T-bet, and suggests novel mechanisms by which T-bet regulates T helper cell differentiation. Specifically, we show that T-bet negatively regulates Th17 lineage commitment via direct repression of the transcription factor interferon regulatory factor-4 (IRF4). An in vivo analysis of the pathogenicity of T-bet deficient T cells demonstrated that Th17 responses were augmented in the absence of T-bet, and we have defined a critical temporal window for T-bet function. The interaction of the two key transcription factors T-bet and IRF4 during the determination of T cell fate choice significantly advances our understanding of the mechanisms underlying the development of pathogenic T cells. ChIP-seq analysis of T-bet in WT and Tbet -/- mice.

2013-12-03 | E-GEOD-40623 | biostudies-arrayexpress

T-bet-depended but IFN-gamma-independent genes in GVHD

Project description:Given T-bet is a master regulator for Th1 differentiation that produce IFN-gamma, underlining mechanisms accounted for the distinct GVHD outcomes caused by T-bet- versus IFN-gamma-deficient donor T cells are unclear. We hypothesize that GVHD is regulated by T-bet-dependent but IFN-gamma-independent molecules. To identify these molecules, we isolated donor T cells from spleen cells of the recipients that were transplanted with WT, T-bet-/- or IFN-gamma-/- CD4 T cells for 7 days. The gene profile of isolated T cells was measured by microarray analysis using GeneChip Mouse Genome 430 2.0 arrays (Affymetrix) according to the manufacturerM-^Rs instructions. Array images were analyzed and processed by robust multi-array average (RMA) procedure.

2014-10-30 | E-MTAB-2198 | biostudies-arrayexpress

ASC controls T-bet-dependent CTL differentiation and defines transplant outcome independent of the inflammasome

Project description:The adaptor protein ASC is known to facilitate caspase-1 activation essential for innate host immunity via the formation of the inflammasome complex - a multi-protein structure responsible for processing IL-1beta and IL-18 to their active moieties. Here we demonstrate that ASC-deficient CD8+ T cells fail to induce graft-versus-host disease (GVHD) and have impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects are the result of an inability to differentiate into fully cytolytic, granzyme B-expressing effector cells, with a developmental bias instead towards CD127+KLRG1- memory CD8+ T cells. These alterations in differentiation are inflammasome-independent, since GVHD lethality and CTL differentiation are not altered in recipients of caspase-1-deficient T cells. We demonstrate that ASC binds to T-bet in CD8+ T and in the absence of ASC, the binding of T-bet to the granzyme B promoter is impaired. Thus, the inhibition of ASC represents an attractive therapeutic target to manipulate transplant outcomes. Single colour, Illumina MouseRef-8 v2.0 Beadarrays.

2016-04-01 | E-GEOD-78755 | biostudies-arrayexpress

RNA-Seq of lymph node fibroblastic reticular cells isolated from bone marrow transplant recipient mice with or without acute Graft-versus-host disease on day 7 or untransplanted control mice

Project description:Acute GVHD is known to damage the structure of peripheral lymphoid organs. This study investigates how peripheral tolerance induction is affected by lymph node stroma damage in the context of graft-versus-host disease. Fibroblastic reticular cells (FRC) were flow sorted on day 7 post allo-BMT in mice developing acute GVHD, transplanted no GVHD-recipients or untransplanted control mice. The single miHA-mismatch female into male transplantation model was used (acute GVHD group: T-cell depleted bone marrow (TCDBM) + HY-specific TCR-transgenic MataHari CD8+ T cells into C57BL/6 male recipients; no GVHD group: TCDBM only).

2020-01-14 | E-MTAB-8255 | biostudies-arrayexpress

Tc17 cells are a pro-inflammatory, plastic lineage of pathogenic CD8+ T-cells that induce GVHD without anti-leukemic effects

2015-09-13 | GSE70931 | GEO

Independent human mesenchymal stromal cell-derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine Graft-versus-Host-Disease model

Project description:Extracellular vesicles (EVs) harvested from conditioned media of human mesenchymal stromal cells (MSCs) suppress acute inflammation in various disease models and promote regeneration of damaged tissues. Following successful treatment of an acute steroid-refractory Graft-versus-Host disease (GvHD) patient with EVs prepared from conditioned media of human bone marrow-derived MSCs, we focus on improving the MSC-EV production for the clinical application. Independent MSC-EV preparations all produced according to a standardized procedure, reveal broad immunomodulatory differences. Only a proportion of our MSC-EV products effectively modulate immune responses in a multi-donor mixed lymphocyte reaction (mdMLR) assay. To explore the relevance of such differences, we have established an optimized mouse GvHD model. The functional testing of selected MSC-EV preparations demonstrate that MSC-EV preparations revealing immunomodulatory capabilities in the mdMLR assay also effectively suppress GvHD symptoms in this model. In contrast, MSC-EV preparations, lacking such in vitro activities, also fail to modulate GvHD symptoms in vivo. Searching for differences of the active and inactive MSC-EV preparations, we failed to identify concrete proteins or miRNAs that could serve as surrogate markers. Thus, standardized MSC-EV production strategies may not be sufficient to warrant manufacturing of MSC-EV products with reproducible qualities. Consequently, given this functional heterogeneity, every individual MSC-EV preparation considered for the clinical application should be evaluated for its therapeutic potency prior to administration to patients. Here, we qualified the mdMLR assay for such analyses.

2023-06-12 | PXD032744 | Pride

Genome-wide regulatory analysis reveals T-bet controls Th17 lineage differentiation through direct suppression of IRF4

2013-12-03 | GSE40623 | GEO

Gene Expression Profiles of PBMC Subsets in Acute GVHD Following Cord Blood Transplantation (IMS v.2)

Project description:In comparison with allogeneic hematopoietic stem cell transplantation using other sources, umbilical cord blood transplantation (UCBT) offers substantial clinical advantages including a lower incidence and severity of acute graft-versus-host disease (GVHD) despite the use of allogeneic UCB stem cells with more disparate HLA. However, detailed pathophysiology of acute GVHD developed after UCBT has not yet been clarified. Here, we examined the roles of inflammatory cells in the pathogenesis of acute GVHD following UCBT, by expression profiling of a total of 615 genes in each of 4 subsets (CD4+, CD8+, CD14+, and CD56+) of peripheral blood mononuclear cells (PBMCs), which were taken from 5 patients with hematologic malignancy, in whom acute GVHD had developed after UCBT. By comparing expression profiles measured during acute GVHD with those measured upon discharge (recovery phase), for each subset of PBMCs, we identified immuno-regulatory genes which were assumed to be linked to the pathogenesis of acute GVHD. Keywords: disease state analysis CD4+, CD8+, CD14+, and CD56+ cell subsets were isolated from the peripheral blood mononuclear cells (PBMCs) of 5 patients with hematologic malignancy, in whom acute GVHD had developed after cord blood transplantation. PBMCs were taken twice â during acute GVHD phase and upon discharge (recovery phase), from each patient. By using a custom-made fibrous oligonucleotide DNA microarray Genopal (Mitsubishi Rayon), we compared expression profiles of 615 unique genes measured during acute GVHD with those measured upon discharge (recovery phase), for each subset of PBMCs.

2010-05-15 | E-GEOD-10513 | biostudies-arrayexpress

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