scholarly journals Effective Destruction of Fas-deficient Insulin-producing β Cells in Type 1 Diabetes

2003 ◽  
Vol 198 (7) ◽  
pp. 1103-1106 ◽  
Author(s):  
Irina Apostolou ◽  
Zhenyue Hao ◽  
Klaus Rajewsky ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Influenza Hemagglutinin ◽  
Insulin Promoter

In type 1 diabetes, autoimmune T cells cause destruction of pancreatic β cells by largely unknown mechanism. Previous analyses have shown that β cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of β cell death in type 1 diabetes. To directly test this hypothesis, we have generated a β cell–specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4+ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of β cells is a dispensable mode of cell death in this disease.

scholarly journals Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Geming Lu ◽  
Francisco Rausell-Palamos ◽  
Jiamin Zhang ◽  
Zihan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Heparan Sulfate ◽  
Dextran Sulfate ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties <i>in vitro</i>. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity <i>in vitro</i>. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

scholarly journals Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity and Ameliorates Type 1 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Geming Lu ◽  
Francisco Rausell-Palamos ◽  
Jiamin Zhang ◽  
Zihan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Heparan Sulfate ◽  
Dextran Sulfate ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

A failure in self-tolerance leads to autoimmune destruction of pancreatic β-cells and type 1 diabetes (T1D). Low molecular weight dextran sulfate (DS) is a sulfated semi-synthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties <i>in vitro</i>. However, whether DS can protect pancreatic β-cells, reduce autoimmunity and ameliorate T1D is unknown. Here we report that DS, but not dextran, protects human β-cells against cytokine-mediated cytotoxicity <i>in vitro</i>. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a pro-inflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in pre-diabetic non-obese diabetic (NOD) mice, and most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases β-cell death, enhances islet heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG) expression and preserves β-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory co-stimulatory molecule programmed death-1 (PD-1) in T-cells, reduces interferon-γ+ CD4+ and CD8+ T-cells and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on β-cell protection, extracellular matrix preservation and immunomodulation can reverse diabetes in NOD mice highlighting its therapeutic potential for the treatment of T1D.

scholarly journals Physiological β Cell Death Triggers Priming of Self-reactive T Cells by Dendritic Cells in a Type-1 Diabetes Model

2003 ◽  
Vol 198 (10) ◽  
pp. 1527-1537 ◽  
Author(s):  
Shannon Turley ◽  
Laurent Poirot ◽  
Masakazu Hattori ◽  
Christophe Benoist ◽  
Diane Mathis
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Mouse Strains ◽  
Β Cells ◽  
Β Cell ◽  
Diabetes Model ◽  
Pancreatic Lymph Nodes ◽  
Antigen Presenting

The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis. This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet β cells encounter antigen-presenting cells (APCs) displaying peptides derived from β cell proteins. We show here that a ripple of physiological β cell death, which occurs at 2 wk of age in all mouse strains, precipitates the arrival of such APCs, and that the relevant APC is a dendritic cell of CD11c+CD11b+CD8α− phenotype. These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

scholarly journals Peptides derived from insulin granule proteins are targeted by CD8+ T cells across MHC Class I restrictions in humans and NOD mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Marie Eliane Azoury ◽  
Mahmoud Tarayrah ◽  
Georgia Afonso ◽  
Aurore Pais ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Class I ◽  
Β Cells ◽  
Β Cell ◽  
Urocortin 3 ◽  
Insulin Granule ◽  
Granule Proteins

The antigenic peptides processed by β cells and presented through surface HLA Class I molecules are poorly characterized. Each HLA variant, e.g. the most common HLA-A2 and HLA-A3, carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8<sup>+</sup> T cells. Several peptides were recognized by CD8<sup>+</sup> T cells within a narrow frequency (1-50/10<sup>6</sup>), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neo-epitopes, generated either via peptide <i>cis</i>-splicing or mRNA splicing, e.g. secretogranin-5 (SCG5)-009. As reported for HLA-A2-restricted peptides, several epitopes originated from β-cell granule proteins, e.g. SCG3, SCG5 and urocortin-3. Similarly, H-2K<sup>d</sup>-restricted CD8<sup>+</sup> T cells recognizing the murine orthologues of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/<i>scid</i> recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.

scholarly journals Peptides derived from insulin granule proteins are targeted by CD8+ T cells across MHC Class I restrictions in humans and NOD mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Marie Eliane Azoury ◽  
Mahmoud Tarayrah ◽  
Georgia Afonso ◽  
Aurore Pais ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Class I ◽  
Β Cells ◽  
Β Cell ◽  
Urocortin 3 ◽  
Insulin Granule ◽  
Granule Proteins

The antigenic peptides processed by β cells and presented through surface HLA Class I molecules are poorly characterized. Each HLA variant, e.g. the most common HLA-A2 and HLA-A3, carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring β-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of β cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8<sup>+</sup> T cells. Several peptides were recognized by CD8<sup>+</sup> T cells within a narrow frequency (1-50/10<sup>6</sup>), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neo-epitopes, generated either via peptide <i>cis</i>-splicing or mRNA splicing, e.g. secretogranin-5 (SCG5)-009. As reported for HLA-A2-restricted peptides, several epitopes originated from β-cell granule proteins, e.g. SCG3, SCG5 and urocortin-3. Similarly, H-2K<sup>d</sup>-restricted CD8<sup>+</sup> T cells recognizing the murine orthologues of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/<i>scid</i> recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.

Neutrophil elastase triggers the development of autoimmune diabetes by exacerbating innate immune responses in pancreatic islets of non-obese diabetic mice

2020 ◽  
Vol 134 (13) ◽  
pp. 1679-1696 ◽  
Author(s):  
Lingling Shu ◽  
Ling Zhong ◽  
Yang Xiao ◽  
Xiaoping Wu ◽  
Yang Liu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Neutrophil Elastase ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Islet Inflammation ◽  
The Impact

Abstract Type 1 diabetes is an autoimmune disease resulted from self-destruction of insulin-producing pancreatic β cells. However, the pathological pathways that trigger the autoimmune destruction remain poorly understood. Clinical studies have demonstrated close associations of neutrophils and neutrophil elastase (NE) with β-cell autoimmunity in patients with Type 1 diabetes. The present study aims to investigate the impact of NE inhibition on development of autoimmune diabetes in NOD mice. NE pharmacological inhibitor (sivelestat) or biological inhibitor (elafin) was supplemented into NOD mice to evaluate their effects on islet inflammation and diabetogenesis. The impact of NE inhibition on innate and adaptive immune cells was measured with flow cytometry and immunohistochemistry. A significant but transient increase in neutrophil infiltration accompanied with elevated NE activity was observed in the neonatal period of NOD mice. Treatment of NOD mice with sivelestat or elafin at the early age led to a marked reduction in spontaneous development of insulitis and autoimmune diabetes. Mechanistically, inhibition of NE significantly attenuated infiltration of macrophages and islet inflammation, thus ameliorating cytotoxic T cell-mediated autoimmune attack of pancreatic β cells. In vitro studies showed that NE directly induced inflammatory responses in both min6 β cells and RAW264.7 macrophages, and promoted macrophage migration. These findings support an important role of NE in triggering the onset and progression of β-cell autoimmunity, and suggest that pharmacological inhibition of NE may represent a promising therapeutic strategy for treatment of autoimmune diabetes.

Use of a systems biology approach to understand pancreatic β-cell death in Type 1 diabetes

2008 ◽  
Vol 36 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Decio L. Eizirik ◽  
Fabrice Moore ◽  
Daisy Flamez ◽  
Fernanda Ortis
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Systems Biology ◽  
Gene Networks ◽  
Nuclear Factor Κb ◽  
Signal Transducer ◽  
Trial And Error ◽  
Β Cells ◽  
Β Cell

Accumulating evidence indicates that β-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that β-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-κB (nuclear factor κB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate β-cell death and the ‘dialogue’ between β-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a ‘trial-and-error’ approach to one that is really mechanistically driven.

scholarly journals Nonlinear Analysis for a Type-1 Diabetes Model with Focus on T-Cells and Pancreatic β-Cells Behavior

2020 ◽  
Vol 25 (2) ◽  
pp. 23
Author(s):  
Diana Gamboa ◽  
Carlos E. Vázquez ◽  
Paul J. Campos
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Cell Population ◽  
Closed Loop ◽  
Pancreatic Β Cell ◽  
Activated Macrophages ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Type-1 diabetes mellitus (T1DM) is an autoimmune disease that has an impact on mortality due to the destruction of insulin-producing pancreatic β -cells in the islets of Langerhans. Over the past few years, the interest in analyzing this type of disease, either in a biological or mathematical sense, has relied on the search for a treatment that guarantees full control of glucose levels. Mathematical models inspired by natural phenomena, are proposed under the prey–predator scheme. T1DM fits in this scheme due to the complicated relationship between pancreatic β -cell population growth and leukocyte population growth via the immune response. In this scenario, β -cells represent the prey, and leukocytes the predator. This paper studies the global dynamics of T1DM reported by Magombedze et al. in 2010. This model describes the interaction of resting macrophages, activated macrophages, antigen cells, autolytic T-cells, and β -cells. Therefore, the localization of compact invariant sets is applied to provide a bounded positive invariant domain in which one can ensure that once the dynamics of the T1DM enter into this domain, they will remain bounded with a maximum and minimum value. Furthermore, we analyzed this model in a closed-loop scenario based on nonlinear control theory, and proposed bases for possible control inputs, complementing the model with them. These entries are based on the existing relationship between cell–cell interaction and the role that they play in the unchaining of a diabetic condition. The closed-loop analysis aims to give a deeper understanding of the impact of autolytic T-cells and the nature of the β -cell population interaction with the innate immune system response. This analysis strengthens the proposal, providing a system free of this illness—that is, a condition wherein the pancreatic β -cell population holds and there are no antigen cells labeled by the activated macrophages.

scholarly journals Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

2020 ◽  
Author(s):  
Heejoo Kim ◽  
Jelena Perovanovic ◽  
Arvind Shakya ◽  
Zuolian Shen ◽  
Cody N. German ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Target Genes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Glucose Levels ◽  
Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

scholarly journals Detecting Insulitis in Type 1 Diabetes with Ultrasound Phase-change Contrast Agents

2020 ◽  
Author(s):  
David G. Ramirez ◽  
Awaneesh K. Upadhyay ◽  
Vinh T. Pham ◽  
Mark Ciccaglione ◽  
Mark A Borden ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Contrast Agents ◽  
Cell Mass ◽  
Nod Mice ◽  
Therapeutic Interventions ◽  
Β Cells ◽  
Β Cell ◽  
Diabetes Onset ◽  
Ultrasound Contrast

AbstractType 1 diabetes (T1D) results from immune infiltration and destruction of insulin-producing β-cells within the pancreatic islets of Langerhans (insulitis), resulting in loss of glucose homeostasis. Early diagnosis during pre-symptomatic T1D would allow for therapeutic intervention prior to substantial loss of β-cell mass at T1D onset. There are limited methods to track the progression of insulitis and β-cell mass decline in pre-symptomatic T1D. During insulitis, the islet microvasculature increases permeability, such that sub-micron sized particles can extravasate and accumulate within the islet microenvironment. Ultrasound is a widely deployable and cost-effective clinical imaging modality. However, conventional microbubble contrast agents are restricted to the vasculature. Sub-micron sized nanodroplet (ND) phasechange agents can be vaporized into micron-sized bubbles; serving as a circulating microbubble precursor. We tested if NDs extravasate into the immune-infiltrated islet microenvironment. We performed ultrasound contrast-imaging following ND infusion in NOD mice and NOD;Rag1ko controls, and tracked diabetes development. We measured the biodistribution of fluorescently labeled NDs, with histological analysis of insulitis. Ultrasound contrast signal was elevated in the pancreas of 10w NOD mice following ND infusion and vaporization, but was absent in both the non-infiltrated kidney of NOD mice and pancreas of Rag1ko controls. High contrast elevation also correlated with rapid diabetes onset. In pancreata of NOD mice, infiltrated islets and nearby exocrine tissue were selectively labeled with fluorescent NDs. Thus, contrast ultrasound imaging with ND phase-change agents can detect insulitis prior to diabetes onset. This will be important for monitoring disease progression to guide and assess preventative therapeutic interventions for T1D.SignificanceThere is a need for imaging methods to detect type1 diabetes (T1D) progression prior to clinical diagnosis. T1D is a chronic disease that results from autoreactive T cells infiltrating the islet of Langerhans and destroying insulin-producing β-cells. Overt disease takes years to present and is only diagnosed after significant β-cells loss. As such, the possibility of therapeutic intervention to preserve β-cell mass is hampered by an inability to follow pre-symptomatic T1D progression. There are immunotherapies that can delay T1D development. However identifying ‘at risk’ individuals, and tracking whether therapeutic interventions are impacting disease progression, prior to T1D onset, is lacking. A method to detect insulitis and β-cell mass decline would present an opportunity to guide therapeutic treatments to prevent T1D.

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