GVHD-mediated Vicious Cascade: Impaired Reconstitution of Immunosuppressive Donor Plasmacytoid Dendritic Cells
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ABSTRACT:
PROVIDER: PRJNA601701 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10902970.fastq.gz | Fastqsanger.gz | |||
| SRR10902971.fastq.gz | Fastqsanger.gz | |||
| SRR10902972.fastq.gz | Fastqsanger.gz | |||
| SRR10902973.fastq.gz | Fastqsanger.gz | |||
| SRR10902974.fastq.gz | Fastqsanger.gz |
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Project description:In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), severe graft-versus-host disease (GVHD) is tied to failed donor plasmacytoid DC (pDC) reconstitution. The mechanism whereby GVHD causes donor pDC defects and the precise role donor pDCs play in GVHD remain poorly understood. pDCs develop from HSCs in successive stages through Flt3 signaling-dependent differentiation, beginning as multi-potent progenitors (MPPs) and later becoming common DC progenitors. We observed that MPPs were critical for sustaining pDCs and were severely depleted during GVHD. Loss of MPPs was associated with decreased amounts of MPP-producing HSCs and mTOR activation-induced cell death of proliferating MPPs. Additionally, GM-CSF derived from alloreactive T cells subverted MPP production of pDCs. Together, GVHD and alloreactive T cells caused donor pDC defects by impairing the generation, maintenance and differentiation of HSCs and MPPs. Importantly, pDCs suppressed the proliferation and expansion of activated autologous CD4+ T cells via a type I-IFN signaling-dependent mechanism. Transfer of donor pDCs early after transplantation repressed GVHD and preserved potent GVL effects, significantly improving the survival of leukemia mice undergoing allo-HSCT. Our findings identify novel strategies that improve the recovery of donor pDCs early after allo-HSCT and thus may represent an effective therapy to control GVHD. Our findings have broad implications for other diseases in which functional DC development is impaired, such as chronic infections, autoimmunity and cancer.
2021-01-06 | GSE143788 | GEO
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
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.
2014-09-09 | GSE61201 | GEO
Project description:Successful hematopoietic cell transplant requires immunosuppression to prevent graft-versus-host disease (GVHD), a lethal, T-cell-mediated post-transplant complication. The phase 3 BMT CTN 1703 trial demonstrated superior GVHD-free/relapse-free survival for post-transplant cyclophosphamide (PT-Cy)-based GVHD prophylaxis versus tacrolimus/methotrexate (Tac/MTX), but did not improve overall survival. To compare T-cell biology between GVHD prophylaxis regimens, 324 patients were co-enrolled onto BMT CTN 1801 (NCT03959241). We quantified T-cell immune reconstitution using multi-modal analysis, including T-cell receptor (TCR) sequencing of 2,359 longitudinal samples (180,432,350 T-cells). Compared to Tac/MTX, PT-Cy was associated with an early, substantial reduction in TCR diversity that was sustained for 2 years. PT-Cy led to a T-cell reconstitution bottleneck, including reduced thymic output and virus-associated TCRs. Decreased D+14 TCR diversity predicted prevention of chronic GVHD, but also correlated with increased moderate-to-severe infections. This study reveals how distinct immunosuppression strategies have significant effects on the global immune repertoire, underpinning post-transplant clinical outcomes.
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Project description:Interleukin 35-producing B-cells (i35-Bregs) suppress autoimmune diseases and IL-35 is immunosuppressive member of IL-12 cytokine family. It is comprised of p35 and Ebi3 subunits which are assumed to be independently secreted proteins that associate in-vivo to form non-covalently linked heterodimeric IL-35. In view of recent reports that p35 and Ebi3 are not secreted as a heterodimer but act as independent anti-inflammatory cytokines, we investigated whether i35-Bregs can suppress GVHD by secreting p35, Ebi3 or heterodimeric IL-35. Surprisingly, i35-Bregs ameliorate and prolong survival of Graft-Versus-Host-Disease (GVHD) via membrane-bound IL-35 and secrete exosomes with membrane-bound IL-35 (i35-exosomes) that upregulate checkpoint inhibitors (PD-1/LAG-3) and induce T-cell exhaustion, thereby rendering allogeneic T-cells less active, with diminished proinflammatory effects. i35-exosomes also propagate infectious tolerance mechanism by binding bystander B-lymphocytes and converting them to IL-35 producers. Adoptive transfer of i35-Bregs or i35-exosomes suppress GVHD through these mechanisms, indicating that i35-Bregs/i35-exosomes combination-immunotherapy maybe effective therapy for GVHD.
2025-02-24 | GSE263242 | GEO
Project description:Reconstitution of stem cells and enhancement of the barrier function of the gastrointestinal (GI) tract is critical to the resolution of intestinal acute graft-versus-host disease (aGvHD). Previously, our group has shown in murine models that type II innate lymphoid cells (ILC2) cells generate proteins in the GI tract that enhanced GI tract barrier function and diminished the expansion and function of pro-inflammatory donor cells when given to allogeneic stem cell transplant recipients. Therefore, the infusion of donor ILC2 cells could treat or prevent GI tract acute GvHD, but for this approach to be clinically applicable, robust expansion of a homogenous population of human ILC2 cells is needed. Here, we describe a method for the rapid expansion of a uniform population of human ILC2 cells which decrease GvHD in (NOD scid gamma mouse) NSG mice. The addition of IL-4 to the culture was critical to prevent the expansion of pro-inflammatory ILC1-like cells. Our approach should allow for the evaluation of human ILC2 cells to treat therapy-resistant GI tract acute GvHD.
2025-07-05 | GSE301228 | GEO
Project description:Reconstitution of stem cells and enhancement of the barrier function of the gastrointestinal (GI) tract is critical to the resolution of intestinal acute graft-versus-host disease (aGvHD). Previously, our group has shown in murine models that type II innate lymphoid cells (ILC2) cells generate proteins in the GI tract that enhanced GI tract barrier function and diminished the expansion and function of pro-inflammatory donor cells when given to allogeneic stem cell transplant recipients. Therefore, the infusion of donor ILC2 cells could treat or prevent GI tract acute GvHD, but for this approach to be clinically applicable, robust expansion of a homogenous population of human ILC2 cells is needed. Here, we describe a method for the rapid expansion of a uniform population of human ILC2 cells which decrease GvHD in (NOD scid gamma mouse) NSG mice. The addition of IL-4 to the culture was critical to prevent the expansion of pro-inflammatory ILC1-like cells. Our approach should allow for the evaluation of human ILC2 cells to treat therapy-resistant GI tract acute GvHD.
2025-07-05 | GSE301227 | GEO
Project description:Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 – 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- γ and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.
2009-09-14 | GSE17995 | GEO
Project description:Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 M-bM-^@M-^S 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- M-NM-3 and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction. B6 recipients were irradiated with 10.0 Gray, administered from a 137 Cs source. Splenocytes from C3H mice were prepared as single cell suspensions in PBS, depleted of red blood cells and counted. 2 M-bM-^@M-^S 3 M-CM-^W 10^7 C3H splenocytes in a volume of 200 M-NM-<l were transplanted into B6 recipients via tail vein injection (4 mice per group per experiment) 4 M-bM-^@M-^S 6 h after irradiation. Mice in the treatment group with anti-ICOSL mAb and their respective controls, received 500 M-NM-<g mAb i. p starting at day 0 or day 3, followed by subsequent injections of 200 M-NM-<g of mAb every other day. At day 4 after transplantation RNA of spleen cells was prepared and subjected to microarray analysis. Combined RNA from allogeneic transplanted mice was hybridized onto 2 independent arrays.
2009-09-14 | E-GEOD-17995 | biostudies-arrayexpress
Project description:Colon biopsies samples were collected after GVHD diagnosis，total RNA was extracted and deep sequenced to compare the gene expression profiles among Normal and acute intestinal GVHD patients
2023-05-02 | GSE165605 | GEO