Similar Datasets
Project description:Tumors induce tolerance towards their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, non-obese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Islet infiltrates of 4 week-old Ins2-CCL21 mice were enriched in naïve CD4+ T cells and compartmentalized within networks of CD45- gp38+ CD31- fibroblastic reticular cell (FRC)-like stromal cells. Importantly, 12 week-old Ins2-CCL21 NOD islets contained FRC-like cells with enhanced expression of β-cell autoantigens and gene expression profiles consistent with regulatory, anti-inflammatory properties and increased contractility. Consistently, transgenic mice harbored fewer autoreactive T cells and higher proportion of Tregs in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that the formation of TLOs in Ins2-CCL21 transgenic islets is critical for regulation of autoimmunity and while the effect is systemic, the induction may be mediated locally by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs associated with islets in T1D in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention. These findings suggest that CCL21 may be exploited for novel immunoregulation approaches to treat autoimmune diabetes.
2019-09-23 | GSE130979 | GEO
Project description:Targeted elimination of senescent beta cells prevents Type 1 Diabetes
| PRJNA483137 | ENA
Project description:Islets from 6-week old NOR and NOD mice were submitted to proteomics analysis to study differences in insulitis and type 1 diabetes development.
2024-05-21 | PXD021475 | Pride
Project description:This dataset consists of single-cell RNA-seq (10X) data from disperesed pancreatic islets of healthy and STZ induced diabetic mice. STZ (Sigma) was injected intraperitoneally in 8-week old male C57BLJ/6 mice at 50 mg/kg for five consecutive days. Islets were isolated from healthy mice and STZ diabetic mice after 100 days of either vehicle or drug treatment.
2020-02-20 | GSE128565 | GEO
Project description:Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D. Here we report that enhancing β-cell mass in female NOD mice early in life (prior to weaning) results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. We observed that a model exhibiting β-cell hyperplasia on the NOD background (NOD-LIRKO) displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival of NOD-LIRKO islets even upon exposure to diabetogenic splenocytes in vivo. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented diabetes development in pre-diabetic NOD mice, while conversely, similar protective outcomes were obtained when NOD-LIRKO splenocytes were adoptively transferred after mixing them with diabetogenic NOD splenocytes in a dose-dependent manner. A significant increase in the splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population in the NOD-LIRKO mice was observed to drive the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with a downregulation of key mediators of cellular function, upregulation of apoptosis and activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data provide novel evidence that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.
2019-03-29 | GSE128315 | GEO
Project description:Background: Activation of stress pathways intrinsic to the β cell are thought to both accelerate β cell death and increase β cell immunogenicity in type 1 diabetes (T1D). However, information on the timing and scope of these responses is lacking. Methods: To identify temporal and disease-related changes in islet β cell protein expression, SWATH-MS/MS proteomics analysis was performed on islets collected longitudinally from NOD mice and NOD-SCID mice rendered diabetic through T cell adoptive transfer. Findings: In islets collected from female NOD mice at 10, 12, and 14 weeks of age, we found a time-restricted upregulation of proteins involved in the maintenance of β cell function and stress mitigation, followed by loss of expression of protective proteins that heralded diabetes onset. Pathway analysis identified EIF2 signaling and the unfolded protein response, mTOR signaling, mitochondrial function, and oxidative phosphorylation as commonly modulated pathways in both diabetic NOD mice and NOD-SCID mice rendered acutely diabetic by adoptive transfer, highlighting this core set of pathways in T1D pathogenesis. In immunofluorescence validation studies, β cell expression of protein disulfide isomerase A1 (PDIA1) and 14-3-3b were found to be increased during disease progression in NOD islets, while PDIA1 plasma levels were increased in pre-diabetic NOD mice and in the serum of children with recent-onset T1D compared to age and sex-matched non-diabetic controls. Interpretation: We identified a common and core set of modulated pathways across distinct mouse models of T1D and identified PDIA1 as a potential human biomarker of β cell stress in T1D.
2023-03-11 | PXD035504 | Pride
Project description:Type 1 diabetes (T1D) is an autoimmune disease triggered by T cell reactivity to protein antigens produced by the β-cells. Here we present a chronological compendium of transcriptional profiles from islets of Langerhans isolated from non-obese diabetic (NOD) mice ranging from 2 wks up to diabetes and compared to controls. Parallel analysis was made of cellular components of the islets. Myeloid cells populated the islets early during development in all mouse strains. This was followed by a type I interferon signature detectable at 4-6 wks of age only in diabetes susceptible mice. Concurrently, CD4 T cells were found within islets, many in contact with intra-islet antigen presenting cells. Early cellular signs of islet reactivity were detected by six wks. By 8 wks, NOD islets contained all major leukocytes populations and an inflammatory gene signature. This work establishes the natural transcriptional signature of T1D and provides a resource for future research. 57 RNA samples isolated from the pancreatic islets of langerhans of experimental mice: 2-18 wk old non-obese diabetic (NOD) and newly diabetic NOD were compared to controls: NOD.RAG-/-, B6.g7 and C57BL/6. There were 3 or 6 biological replicates per condition. All mice were female. All data was normalized using RMA in Arraystar. Data table includes normalized probe intensity for every probe.
2013-01-28 | E-GEOD-41203 | biostudies-arrayexpress
Project description:Autoreactive CD8+ T cell plays a key role in the pathogenesis of Type 1 diabetes (T1D), but the antigen spectrum that activate autoreactive CD8+ T cells is still not completely clear. Endoplasmic reticulum stress（ERS）has been implicated in the generation of β cell autoantigens and the enhanced immune visibility of β cells to autoreactive T cells. Here, we in-depth analyzed the major histocompatibility complex class I (MHC-I) associated immunopeptidome (MIP) of islets β cell under steady-state and ERS-state, and found couples of peptides exclusively present in the MIP of β cell line under ERS state. Among them, peptide OTUB258-66 derived from ubiquitin thioesterase OTUB2 showed immunodominance in NOD mice, and autoreactive CD8+ T cells targeting OTUB258-66 were diabetogenic in NOD mice. High glucose intake upregulated the expression of OTUB2 in the pancreas and amplified the OTUB258-66-specific CD8+ T cell response in NOD mice. Repeated administration with OTUB258-66 significantly reduced the incidence of T1D in NOD mice. This study not only provides an explanation for the role of ERS induced by environmental factors such as high glucose intake in promoting β cell autoimmune injury, but also provides a novel ERS-associated β cell autoantigens for developing specific immune intervention in prevention and treatment of T1D.
2024-05-24 | PXD041227 | Pride
Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Replacing 1/5th of the HC with gluten restores high T1D to NOD mice. We hypothesized that gluten might promote inflammation in the islets. We used TCR sequencing to characterize the clonal frequency of infiltrating T cells from the pancreatic islets of Langerhans of NOD mice fed a 20% HC diet or a 16% HC + 4% gluten diet.
2023-01-04 | GSE218336 | GEO
Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Replacing 1/5th of the HC with gluten restores high T1D to NOD mice. We hypothesized that gluten might promote inflammation in the islets. We used single cell RNA sequencing (scRNAseq) to characterize and contrast the transcriptional profiles of endocrine cells and islet infiltrating leukocytes from the pancreatic islets of Langerhans of NOD mice fed a 20% HC diet or a 16% HC + 4% gluten diet.
2023-01-04 | GSE217493 | GEO