The Atlas of Immune Infiltrates in Islet Cell Allo-transplantation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA817208 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18357942_1.fastq.gz | Fastqsanger.gz | |||
| SRR18357942_2.fastq.gz | Fastqsanger.gz | |||
| SRR18357943_1.fastq.gz | Fastqsanger.gz | |||
| SRR18357943_2.fastq.gz | Fastqsanger.gz |
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Project description:Islet transplantation to treat the late stage of T1DM patients has made some inspiring success recently in clinical trials. However, most of patients underwent a decline of islet cell graft in one to three years due to chronic immune rejection. Although the mechanisms of immune cells including macrophages, dendritic cells (DCs), neutrophils, natural killer cells (NKs), B cells, T cells that mediate immune rejection have been investigated, the overall characteristics of immune infiltrates in islet allografts remain unclear. Single-cell RNA sequencing (scRNA-seq) has provided us with new opportunities to study the molecular characteristics of the immune microenvironment in islet transplants. In the present study, we used scRNA-seq to comprehensively analyze the immune heterogeneity in islet graft, and compared the variances regarding to transcriptomal profiling and immune atlas between syngeneic islet transplantation and allograft.
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Project description:The intrahepatic milieu is inhospitable to intraportal islet allografts, limiting their applicability to ameliorate Type 1 Diabetes (T1D). Islet viability in the subcutaneous space represents an unfulfilled paradigm that is crucial to ensure widespread adoption and safety of clinical islet transplantation. Herein we report that human islets transplanted subcutaneously uniformly promote long-term euglycemia when admixed with a device-free Islet Viability Matrix (IVM), through a previously unknown anti-apoptotic mechanism.
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Project description:Acute graft versus host disease is a serious condition caused by allo-reactive donor CD4+ T cells from allogenic hematopoietic stem cell transplantation. To understand the developmental relationships between T-helper states in mesenteric lymph nodes (mLN), TCR transgenic CD4+ T cells specific for a single allo-peptide (TEa cells) from mice were recovered at Days 0, 1, 2, 3, and 4 from mLN, and Day 5 from the gut and underwent processing to generate scRNA-seq dataset. TEa cells were also recovered at Day 5 from mLN and were either treated with and without IEL-isolation pre-digestion buffer as controls.
2020-06-06 | E-MTAB-9125 | biostudies-arrayexpress
Project description:Mouse pancreatic islet scRNA-seq integrated atlas encompassing different ages, sexes, chemical stress leading to dedifferentiation, and diabetes models with corresponding treatments. Two datasets (sub-series) were newly generated for the atlas.
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Project description:Type 1 diabetes (T1D) results from insulin insufficiency due to the loss or dysfunction of pancreatic beta cells following T cell-mediated autoimmune attack. Currently, the only long-term therapy is daily exogenous insulin replacement. The ideal curative approach is the durable restoration of functional islets via transplantation with or without immunosuppression or immune modulation. To date, the limiting factors impeding realization of this goal is the lack of a cost effective and limitless source of high-quality islets suitable for transplantation and the ability to provide long-term islet graft acceptance without prolonged need for deleterious immunosuppression. Ongoing clinical trials are testing the suitability of islets derived from human induced pluripotent stem cells (iPSC); however, long-term acceptance of these or any other islet graft will require a clinically effective therapeutic strategy to prevent engrafted islet destruction by pre-existing islet-antigen specific T cells. While current immunomodulatory strategies focus on autologous T regulatory (Treg) cell expansion or the use of broad immunosuppression, here we demonstrate in the NOD mouse model for T1D that autologous islet graft acceptance can be achieved by the targeted elimination of (re)-activated islet-reactive CD4+ and CD8+ T effector (Teff) cells in the initial post-transplantation period by using a short-acting, combination therapy that results in the elimination of islet-reactive Teff cells by exacerbation of their natural DNA damage response (DDR) to drive apoptosis while at the same time maintaining endogenous Treg cell function and reducing the effector function of residual islet-reactive T cells.
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Project description:From the past reports, we hypothesized that spleen is an ideal site for inducing regeneration of transplanted islets, and leading to reduce the required number of islets for ameliorating the hyperglycemia of diabetic recipients in mice. In order to confirm this hypothesis, we performed 25 islets transplantation into spleen (SP25); it was not enough number to ameliorate the hyperglycemia of recipient mice, with 100 islets transplantation into beneath the kidney capsule (KC100) to maintain recipients' blood glucose normoglycemic temporary. All recipient mice (n=11) became normoglycemic after receiving SP25 with KC100. On 240 days after transplantation, we performed nephrectomy for removing islet grafts in the kidney. After nephrectomy, 8 of 11 mice remained normoglycemic, and 3 of 11 mice' non-fasting blood glucose levels were maintained around 300 mg/dL. On 290 days after transplantation (50 days after nephrectomy), all recipient mice received splenectomy to remove islet grafts in the spleen. All mice became hyperglycemic after splenectomy, indicating that intra-splenic islet grafts maintained the blood glucose levels of diabetic recipient mice. In order to investigate the gene expression associated with islets engraftment in the spleen, microarray studies were performed in comparison of the Tlx-1 (Hox11) related gene expression profiles of Sample 1, Sample 2 and Sample 3.
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Project description:The aim of this study is to assess the Fecal Microbiota Transplantation (FMT) efficacy in the prevention of allogeneic hematopoietic stem cell transplantation (allo-HSCT) complications and particularly Graft versus Host Disease (GvHD).
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Project description:Loss of pancreatic beta cells is the central feature of all forms of diabetes. Current therapies fail to halt the declined beta cell mass. Thus, strategies to preserve beta cells are imperatively needed. In this study, we identified paired box 6 (PAX6) as a critical regulator of beta cell survival. Under diabetic conditions, the human beta cell line EndoC-bH1, db/db mouse and human islets displayed dampened insulin and incretin signalings and reduced beta cell survival, which were alleviated by PAX6 overexpression. Adeno-associated virus (AAV)-mediated PAX6 overexpression in beta cells of streptozotocin-induced diabetic mice and db/db mice led to a sustained maintenance of glucose homeostasis. AAV-PAX6 transduction in human islets reduced islet graft loss and improved glycemic control after transplantation into immunodeficient diabetic mice. Our study highlights a previously unappreciated role for PAX6 in beta cell survival and raises the possibility that ex vivo PAX6 gene transfer into islets prior to transplantation might enhance islet graft function and transplantation outcome.
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Project description:BACKGROUND: Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase I clinical trial of Treg cell therapy in living donor renal transplantation, the ONE Study (NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression. METHODS: We present seven years of follow-up data on patients treated with adoptive Treg cell therapy early post-transplantation, who exhibited focal lymphocytic infiltrates on a nine-month protocol biopsy. We phenotyped their adoptively transferred and peripherally circulating Treg compartments using CITEseq and investigated the focal lymphocytic infiltrates with spatial proteomic and transcriptomic technologies. FINDINGS: Graft survival rates were not significantly different between Treg-treated patients and the control reference group. None of the Treg-treated patients experienced clinical rejection episodes or developed de novo donor-specific antibodies, and three of ten successfully reduced their immunosuppression to tacrolimus monotherapy. All Treg-treated patients who underwent a protocol biopsy nine months post-transplantation exhibited focal lymphocytic infiltrates. Spatial profiling analysis revealed a prominent CD20+ B cell signature within cell therapy-associated immune infiltrates, distinct from the pro-inflammatory myeloid signature typically associated with the rejection biopsies. A regulatory gene expression program (IKZF2, IL10, PD-L1, TIGIT) characterized the cell therapy-associated immune infiltrates at a transcriptional level. CONCLUSIONS: We demonstrate for the first time that immune cell infiltrates in transplanted kidneys can occur following adoptive Treg cell therapy in humans, potentially facilitating within-graft T:B cell interactions that promote local immune regulation. FUNDING: 7th EU Framework Programme, Grant/Award Number: 260687; National Institute for Health Research (NIHR).
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Project description:The prediction of acute graft-versus-host disease (aGvHD) post allogeneic hematopoietic stem cell transplantation (allo-HSCT) is critical for treatment decisions. The granulocytic myeloid-derived suppressor cells (G-MDSCs) show a fast recovery post-transplantation and constituted the major part of peripheral blood in the early phase after allo-HSCT. These cells were previously believed to exhibit immunosuppressive properties. However, they also promote inflammation under specific conditions. Thus, we conducted a comprehensive study of G-MDSCs from 82 patients after allo-HSCT within 90 days to elucidate the role of them in post-transplantation immunity. Strikingly, our results showed that G-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing aGvHD. Besides, adoptive transfer of G-MDSCs from patients into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs showed immunosuppressive features, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that a total of 1445 genes were differentially expressed. Genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. After the genetic overlap analysis, DERL1 may be the hub-gene. Our findings elucidate the alteration in the immune characteristics of G-MDSCs within the first 90 days post allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 could serve as a predictive indicator for aGvHD.
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