ScRNA-seq of lymph node stromal cells from naïve mice and heart allograft transplanted mice with/without anti-CD40L
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE262918 | GEO | 2025/04/02
REPOSITORIES: GEO
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Project description:Balb/c donor hearts were transplanted into C57/BL6 recipients as previously described (Corry et al, 1973). Recipient mice were treated with 250μg anti-CD40L mAb for tolerance induction on days 0, 2, and 4 as previously described (Jiang et al., 2011) or left untreated. On day 5 after transplantation graft infiltrating myeloid subsets were isolated using fluorescence activated cell sorting (FACS). Affymetrix Mouse Gene arrays were run in triplicate with the samples of interest. Raw CEL file data from Affymetrix Expression Console were background corrected, normalized, and summarized using RMA. 18 Samples, 9 treated and 9 untreated, 3 replicates each
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Project description:Background: While heart transplantation is the standard treatment for heart failure, both acute and chronic transplant rejection frequently occur. Since the modulation of protein phosphatase PP2A activity is critical for tissue and organ homeostasis under physiological and pathophysiological conditions, PP2A may also affect the ability to tolerate transplanted organs. Here we demonstrate that administration of a novel class of small molecule activators of PP2A (SMAPs) prolonged cardiac allograft survival in a mouse heterotopic heart transplantation model. Mechanistically, SMAPs effectively suppressed the inflammatory immune response while increasing Treg population in the allografts, findings corroborated by functional analysis of RNAseq data derived from Tregs of treated splenic tissue. Importantly, SMAPs further prolonged CTLA4-Ig (an immunosuppressive agent utilized in organ transplantation)-induced cardiac rejection tolerance and extended allograft survival. SMAPs also strongly mitigated cardiac allograft vasculopathy as evidenced by a marked reduction of neointimal hyperplasia and smooth muscle cell proliferation. Mechanistic studies implicate SMAPs elicited suppression of MEK/ERK pathways as a unifying mechanism for the aforementioned effects in Tregs and SMCs. These findings highlight the potential of PP2A activation in improving alloengraftment in heart transplantation and add knowledge to the phosphatase driven regulation of the immune system in the context of organ transplantation.
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Project description:Solid organ transplantation in the mouse is a powerful research tool that has provided a pathway to find important mechanistic insights into the regulation of allograft injury, allograft immunopathology, and transplant rejection/tolerance, and that has unique advantages over transplantation in larger species, due to the well characterization of mouse genome and availability of genetically modified animals. However, setup of mouse liver, heart and kidney transplantation is a technically demanding surgical procedure, especially the orthotopic liver transplantation in mouse. Here, we performed Microwell-based single cell RNA-seq of three mouse organ transplantation models (liver, heart and kidney). Comparison of lymphocytes, parenchyma cells and peripheral blood mononuclear cells in liver, heart and kidney revealed distinct immune microenvironment at acute rejection and tolerance state respectively. Single-cell transcriptome analysis of mouse allograft without immunosuppressive drugs provided rich resources to help understand functioning solid-organ transplantation in human.
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Project description:In order to study the changes of liver protein level in mice with acute cardiac rejection, we established a mouse model of ectopic heart transplantation. According to the matching relationship between recipient and donor, they were divided into the following two groups: allograft group (ALLO), BALB/ C hearts were transplanted into C57BL/6J recipients with complete mismatch of major histocompatibility complex; In the syngeneic transplantation group (ISO), C57BL/6J hearts were transplanted into MHC-matched C57BL/6J recipients. On day 6 after mouse heart transplantation, livers were obtained from recipient mice in the allograft group (n = 3) and from recipient mice in the syngeneic (ISO) group (n = 3). A series of techniques such as protein extraction, enzyme digestion, TMT labeling, HPLC classification, liquid chromatography-mass spectrometry tandem analysis, database search and bioinformation analysis were used to study the quantitative proteome of samples.
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Project description:Non-hematopoietic lymph node stromal cells (LNSCs) regulate lymphocyte trafficking, survival, and function for key roles in host defense, autoimmunity, alloimmunity, and lymphoproliferative disorders. However, study of LNSCs in human diseases is complicated by a dependence on viable lymphoid tissues, which are most often excised prior to establishment of a specific diagnosis. Here, we demonstrate that cryopreservation can be used to bank lymphoid tissue for the study of LNSCs in human disease. Using human tonsils, lymphoid tissue fragments were cryopreserved for subsequent enzymatic digestion and recovery of viable non-hematopoietic cells. Flow cytometry and single-cell transcriptomics identified comparable proportions of LNSC cell types in fresh and cryopreserved tissue. Moreover, cryopreservation had little effect on transcriptional profiles, which showed significant overlap between tonsils and lymph nodes. The presence and spatial distribution of transcriptionally defined cell types was confirmed by in situ analyses. Our broadly applicable approach promises to greatly enable research into the roles of LNSC in human disease.
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Project description:Xenotransplantation holds the promise of providing an unlimited supply of donor organs for terminal patients with organ failure. The gal carbohydrate results in rejection of wild type pig grafts, however, chimerism established by expression of the GalT gene prior to transplantation in GalT knockout mice results in tolerance to Gal+ heart grafts. We used microarrays in order to further understand the early events that occur within grafts that demonstrate tolerance. Experiment Overall Design: The GalT BMT recipient is a GalT knockout mouse which recieved GalT gene transduced allo-bone marrow cells transplantation after sublethal irradiation. A heart of wild type C57BL/6 was heterotopically transplanted into the recipient after GalT BMT. Syngeneic Control recipient is a wild type C57BL/6 transplanted a heart of wild C57BL/6.
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Project description:Cellular rejection after heart transplantation imparts significant morbidity and mortality. Current immunosuppressive strategies are imperfect, target recipient T-cells, and have adverse effects. The innate immune response plays an essential role in the recruitment and activation of T-cells. Targeting the donor innate immune response would represent the earliest interventional opportunity within the immune response cascade. There is limited knowledge regarding donor immune cell types and functions in the setting of cardiac transplantation and no current therapeutics exist for targeting these cell populations. Distinct populations of donor and recipient macrophages co-exist within the transplanted heart. Donor CCR2+ macrophages are key mediators of allograft rejection and deletion of MYD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograft survival. This highlights the therapeutic potential of donor heart-based interventions.
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Project description:Immune responses induced by ongoing and/or past infections prevent the establishment of transplantation tolerance in experimental animal models. How host-pathogen interactions influence allograft tolerance in humans has not been investigated before. The spontaneous development of operational tolerance in liver transplant recipients with chronic hepatitis C virus (HCV) infection constitutes a unique setting to address this question. We conducted a clinical trial of immunosuppression withdrawal in stable HCV-infected liver recipients to elucidate: i) the mechanisms through which allograft tolerance is established in the presence of an ongoing inflammatory response; and ii) how is influenced by anti-HCV heterologous immune responses. Enrolled patients gradually discontinued their immunosuppressive drugs over 6-9 months, and those who maintained normal allograft status 12 months after drug withdrawal were considered operationally tolerant. Successful drug withdrawal was associated with intra-hepatic over-expression of type I interferon and immune-regulatory genes, and correlated with an expansion of exhausted PD1/CTLA4/2B4-positive HCV-specific circulating CD8+ T cells. These findings were already present before immunosuppression was discontinued and were specific for HCV infection. In contrast, the magnitude of HCV-induced inflammatory gene expression and the scope of anti-HCV effector T cell responses did not influence drug withdrawal outcome. Our data indicate that in humans persistent viral infections do not necessarily preclude the development of transplantation tolerance. At least in HCV-infected liver allografts, mechanisms associated with the capacity of the virus to evade adaptive immunity could contribute to the restraining of alloimmune responses and the establishment of transplantation tolerance. Transcriptomic study from the following liver tissue samples: 12 tolerant before immunosuppression (IS), 13 non-tolerant before IS, 4 from non-tolerant at the time of rejection, 13 from tolerant patients 12 months after IS discontinuation. Additionally, 8 liver tissue samples obtained from healthy living liver donors undergoing partial hepatectomy were included as non-transplanted controls.
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