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Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [15065R]

ABSTRACT: Lymphocyte subsets (CD8, CD4 Tconv, CD4 Treg) were sorted from patients' peripheral blood obtained on day 28 after matched-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy) as a single agent GVHD prophylaxis (NCT00809276). Cohort of patients developed GVHD, or remained GVHD-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182610 | GEO | 2021/09/28

REPOSITORIES: GEO

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Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17618R]

Project description:Lymphocyte subsets (CD8, CD4 Tconv, CD4 Treg) were sorted from patients' peripheral blood obtained 180 days after matched-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy) as a single agent GVHD prophylaxis (NCT00809276). Cohort of patients developed GVHD, or remained GVHD-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD.

2021-09-28 | GSE182678 | GEO

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17941R-18740R]

Project description:Lymphocyte subsets (CD8, CD4 Tconv, NK cells) were sorted from patients' peripheral blood obtained on day 28 after haploidentical-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy), tacrolimus, and MMF as GVHD prophylaxis (NCT00796562). Cohort of patients developed GVHD, or remained GVHD-free. Cohort of patients developed disease relapse, or remained relapse-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD and relapse.

2021-09-28 | GSE182612 | GEO

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

Project description: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.

2024-04-30 | GSE255545 | GEO

Azacitidine mitigates GvHD via its differential effects on expansion of nTregs in vivo.

Project description:Azacitidine (AzaC) mitigates Graft vs. Host Disease (GVHD) in both murine preclinical transplant models and in human clinical trials while maintaining a robust Graft vs. Leukemia (GVL) effect. Previous studies have failed to investigate the role of natural Tregs on the mitigation of GVHD by AzaC; instead focusing on the generation of suppressive regulatory T cells (Tregs, CD4+CD25+FOXP3+) through the in vivo conversion of alloreactive donor T effectors (Teff CD4+ CD25-, FOXP3-) and the direct anti-proliferative effects of AzaC on allogeneic T cells. Using B6.Foxp3DTR/GFP mice in which Tregs can be specifically ablated through administration of Diphtheria toxin, we demonstrate that nTregs are required in the donor graft for AzaC to optimally protect against GvHD and that nTregs, unlike T effectors (Teff, CD3+FOXP3-), are resistant to the anti-proliferative effects of AzaC. Gene expression analysis identified the potent cell cycle inhibitor, p21, was significantly upregulated in Teff but not nTregs after treatment with AzaC. Furthermore, we demonstrate that Teff cells deficient in p21 are less sensitive to the antiproliferative effects of AzaC. These results, demonstrate that nTregs are essential for AzaC to fully protect against GvHD and have important clinical implications for future clinical trials testing AzaC as a novel method of GVHD prophylaxis in man.

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Addition of IL-6 inhibition to standard GVHD prophylaxis to prevent GVHD after allogeneic stem cell transplantation

Project description:BACKGROUND - IL-6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem cell transplantation (alloSCT) and is an attractive therapeutic target. METHODS - A registered phase I/II study (ACTRN12612000726853) of IL-6 receptor (IL-6R) neutralizing antibody administration on day -1 to patients receiving full or reduced-intensity conditioning (RIC) and alloSCT from HLA-matched sibling or unrelated donors with standard cyclosporin and methotrexate GVHD prophylaxis. The primary endpoint was incidence of grade II-IV acute GVHD. Outcomes were compared to a non-randomized but contemporaneous group of study patients receiving the same alloSCT in the absence of IL-6R mAb. FINDINGS - Cytokine and pharmacokinetic analysis confirmed transient IL-6 dysregulation in the first month after alloSCT with complete inhibition following IL-6R mAb administration. With median follow up of 497 days, the incidence of grade II-IV GVHD was 12.5% in recipients of IL-6R inhibition (n = 48) versus 41.5% in the (n = 53) control cohort (P = 0.001). Low rates of acute GVHD were noted in patients receiving IL-6R inhibition relative to control patients following both myeloablative (12.5% vs. 46.4%, P = 0.03) and RIC (12.5% vs. 36.0%, P = 0.04). The incidence of severe (grade III/IV) acute GVHD was 4.2% in recipients of IL-6R inhibition versus 20.8% in the control cohort (P = 0.012). Relapse and chronic GVHD were unchanged. Immune reconstitution was preserved in recipients of IL-6R inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION - IL-6 is the principal detectable and dysregulated cytokine secreted after alloSCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution and a sustained graft-versus-leukemia effect. Single colour, Illumina Human HT12v4 Beadarrays.

2014-09-09 | E-GEOD-61201 | biostudies-arrayexpress

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning

Project description:Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning

| PRJNA757406 | ENA

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [15065R]

Project description:Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [15065R]

| PRJNA757410 | ENA

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17618R]

Project description:Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17618R]

| PRJNA757412 | ENA

Single cell RNA sequencing of mouse donor T cells after graft-versus-host disease (GVHD) model

Project description:Lethally irradiated mice were transferred with bone marrow cells together with allogeneic Treg cells isolated from CD226+/+ TIGIT+/+, CD226-/- TIGIT+/+, CD226+/+ TIGIT-/-, or CD226-/- TIGIT-/- mice, followed by allogeneic wild-type Tconv cells two days later to induce acute GVHD. We performed scRNA sequencing of donor T cells isolated from the spleen of recipient mice eight days after GVHD induction.

2021-05-18 | GSE155250 | GEO

Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17941R-18740R]

Project description:Signatures of GVHD and Relapse after Post-Transplant Cyclophosphamide Revealed by Immune Profiling and Machine Learning [17941R-18740R]

| PRJNA757413 | ENA

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