Linking erythropoietin to regulatory T-cell-dependent allograft survival through myeloid cells
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PROVIDER: PRJNA819094 | ENA |
REPOSITORIES: ENA
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Project description:Erythropoietin (EPO) has multiple functions beyond stimulating erythrocytosis, including modulation of T cell immunity. Effects EPO in transplantation and associated mechanisms remain incompletely understood. We analyzed outcomes and performed cellular and molecular mechanistic assessments in murine wild type (WT) and conditional EPO receptor (EPOR) knockout recipients of cardiac allografts. In translational studies, we tested EPO’s effects in a non-human primate system.
2023-03-01 | GSE199270 | GEO
Project description:Trained immunity suppression determines kidney allograft survival
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Project description:Trained immunity suppression determines kidney allograft survival [ChIP]
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Project description:The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
2024-11-04 | GSE280787 | GEO
Project description:The innate immune system plays an essential role in regulating the immune responses to kidney transplantation, but the mechanisms through which innate immune cells influence long-term graft survival are unclear. The current study highlights the vital role of trained immunity in kidney allograft survival. Trained immunity describes the epigenetic and metabolic changes that innate immune cells undergo following an initial stimulus, allowing them have a stronger inflammatory response to subsequent stimuli. We stimulated healthy peripheral blood mononuclear cells with pretransplant and posttransplant serum of kidney transplant patients and immunosuppressive drugs in an in vitro trained immunity assay and measured tumor necrosis factor and interleukin 6 cytokine levels in the supernatant as a readout for trained immunity. We show that the serum of kidney transplant recipients collected 1 week after transplantation can suppress trained immunity. Importantly, we found that kidney transplant recipients whose serum most strongly suppressed trained immunity rarely experienced graft loss. This suppressive effect of posttransplant serum is likely mediated by previously unreported effects of immunosuppressive drugs. Our findings provide mechanistic insights into the role of innate immunity in kidney allograft survival, uncovering trained immunity as a potential therapeutic target for improving graft survival.
2024-11-04 | GSE280903 | GEO
Project description:Recent studies have demonstrated that both mouse and human alpha beta TCR(+)CD3(+)NK1.1(-)CD4(-)CD8- double-negative regulatory T (DN Treg) cells can suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells. To identify molecules involved in DN Treg cell function, we generated a panel of murine DN Treg clones, which specifically kill activated syngeneic CD8+ T cells. Through serial cultivation of DN Treg clones, mutant clones arose that lost regulatory capacity in vitro and in vivo. Although all allogeneic cardiac grafts in animals preinfused with tolerant CD4/CD8 negative 12 DN Treg clones survived over 100 days, allograft survival is unchanged following infusion of mutant clones (19.5 +/- 11.1 days) compared with untreated controls (22.8 +/- 10.5 days; p < 0.001). Global gene expression differences between functional DN Treg cells and nonfunctional mutants were compared. We found 1099 differentially expressed genes (q < 0.025%), suggesting increased cell proliferation and survival, immune regulation, and chemotaxis, together with decreased expression of genes for Ag presentation, apoptosis, and protein phosphatases involved in signal transduction. Expression of 33 overexpressed and 24 underexpressed genes were confirmed using quantitative real-time PCR. Protein expression of several genes, including Fc epsilon RI gamma subunit and CXCR5, which are >50-fold higher, was also confirmed using FACS. These findings shed light on the mechanisms by which DN Treg cells down-regulate immune responses and prolong cardiac allograft survival. Type 2 experiment where functional DN T-reg cells (CN4 or TN12) were cy-3 labeled and co-hybridized with non-functional mutant cell lines (CN4.8 or CN12.8). Used 100 ug total-RNA each channel and no amplifaction. A transcript identification design type characterizes the length and position of transcripts and allows identification of all forms of transcripts in the genome. Using regression correlation
2005-07-29 | E-GEOD-3024 | biostudies-arrayexpress
Project description:Recent studies have demonstrated that both mouse and human alpha beta TCR(+)CD3(+)NK1.1(-)CD4(-)CD8- double-negative regulatory T (DN Treg) cells can suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells. To identify molecules involved in DN Treg cell function, we generated a panel of murine DN Treg clones, which specifically kill activated syngeneic CD8+ T cells. Through serial cultivation of DN Treg clones, mutant clones arose that lost regulatory capacity in vitro and in vivo. Although all allogeneic cardiac grafts in animals preinfused with tolerant CD4/CD8 negative 12 DN Treg clones survived over 100 days, allograft survival is unchanged following infusion of mutant clones (19.5 +/- 11.1 days) compared with untreated controls (22.8 +/- 10.5 days; p < 0.001). Global gene expression differences between functional DN Treg cells and nonfunctional mutants were compared. We found 1099 differentially expressed genes (q < 0.025%), suggesting increased cell proliferation and survival, immune regulation, and chemotaxis, together with decreased expression of genes for Ag presentation, apoptosis, and protein phosphatases involved in signal transduction. Expression of 33 overexpressed and 24 underexpressed genes were confirmed using quantitative real-time PCR. Protein expression of several genes, including Fc epsilon RI gamma subunit and CXCR5, which are >50-fold higher, was also confirmed using FACS. These findings shed light on the mechanisms by which DN Treg cells down-regulate immune responses and prolong cardiac allograft survival. Type 2 experiment where functional DN T-reg cells (CN4 or TN12) were cy-3 labeled and co-hybridized with non-functional mutant cell lines (CN4.8 or CN12.8). Used 100 ug total-RNA each channel and no amplifaction. A transcript identification design type characterizes the length and position of transcripts and allows identification of all forms of transcripts in the genome. Keywords: transcript_identification_design
2005-07-29 | GSE3024 | GEO
Project description:Immune tolerance is an active state of unresponsiveness of the immune system to antigens (Ags) that have the potential to induce an immune response1. Such tolerance is beneficial in avoiding autoimmunity and rejection of organ transplants, but detrimental in cancer2. Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis3 and cross-presenting abilities4, resulting in T cell-mediated immunity5 or tolerance6-10. However, the mechanisms underlying the tolerogenic function of cDC1s remain largely unknown. Here, we show that the erythropoietin receptor (EpoR) acts as a critical switch that determines the tolerogenic state of cDC1s and the threshold of Ag-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance11,12, EpoR+ cDC1s induce donor-specific CD4+FoxP3+ regulatory T cells (Tregs), and conditional knockout of EpoR in cDC1s abrogates Ag-specific Treg induction, resulting in allograft rejection. In the steady state, EpoR+ migratory cDC1s control Ag-specific Treg induction in peripheral lymph nodes (LNs). In cancer, EpoR is expressed on both tumor Ag-carrying, tumor-infiltrating cDC1s, as well as migratory cDC1s in tumor-draining LNs (tdLNs). Loss of EpoR from cDC1s leads to tumor reduction by enhancing tumor Ag-specific CD8+ T cell priming and generating more precursor exhausted T cells13 in tdLNs, preserving CD8+ T cell precursor-like features and effector function, and reducing Tregs in the tumor. Thus, targeting EpoR on cDC1s to induce or inhibit immune tolerance should enable new ways to treat a variety of diseases.
2024-03-01 | GSE253056 | GEO
Project description:Mouse monocytes exposed to M-CSF and IFN-M-NM-3 were driven to a suppressor phenotype over a seven day culture period. The resulting regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarised macrophages and monocyte-derived DCs. M regs completely suppressed polyclonal T cell proliferation through an inducibile nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs were found to eliminate cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5x10^6 donor-strain M regs prior to transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c and C57BL/6-to-BALB/c strain combinations; this graft-protective effect was alloantigen-specific. M regs from Nos2-deficient mice did not prolong allograft survival, proving that M reg function in vivo is iNOS-mediated and dependent on living cells. Co-treatment with 1 mg/kg/day rapamycin for 10 days post-transplant markedly enhanced the effect of M regs. In untransplanted C57BL/6 recipients, M regs of BALB/c origin were detectable for up to 2 weeks post-infusion. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of tolerogenic macrophages, which resemble human M regs in their derivation, phenotype and in vitro functions. The dataset comprises 36 samples divided into twelve sample groups each representing a certain monocyte/macrophage subtype
2013-12-21 | E-GEOD-32690 | biostudies-arrayexpress