scholarly journals Pancreatic β-Cells Regeneration During the Reversal of Autoimmune Diabetes in Nod Mice.

2011 ◽  
Vol 4 (3) ◽  
pp. 387-388
Author(s):  
Takuma Hayashi ◽  
Keyword(s):  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Pancreatic Β Cells

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.

Dynamic interaction between T cell-mediated β-cell damage and β-cell repair in the run up to autoimmune diabetes of the NOD mouse

2005 ◽  
Vol 21 (2) ◽  
pp. 201-211 ◽  
Author(s):  
Sankaranand S. Vukkadapu ◽  
Jenine M. Belli ◽  
Koji Ishii ◽  
Anil G. Jegga ◽  
John J. Hutton ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Activation ◽  
Autoimmune Diabetes ◽  
Cellular Adhesion ◽  
Nod Mouse ◽  
Gene Control ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

In type 1 diabetes mellitus (T1DM), also known as autoimmune diabetes, the pathogenic destruction of the insulin-producing pancreatic β-cells is under the control of and influenced by distinct subsets of T lymphocytes. To identify the critical genes expressed by autoimmune T cells, antigen presenting cells, and pancreatic β-cells during the evolution of T1DM in the nonobese diabetic (NOD) mouse, and the genetically-altered NOD mouse (BDC/N), we used functional genomics. Microarray analysis revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin (IL)-17, and islet cell regenerating genes, Reg3α, Reg3β, and Reg3γ. Our data indicate that progression to insulitis was connected to marked changes in islet antigen expression, β-cell differentiation, and T cell activation and signaling, all associated with tumor necrosis factor-α and IL-6 expression. Overt diabetes saw a clear shift in cytokine, chemokine, and T cell differentiation factor expression, consistent with a focused Th1 response, as well as a significant upregulation in genes associated with cellular adhesion, homing, and apoptosis. Importantly, the temporal pattern of expression of key verified genes suggested that T1DM develops in a relapsing/remitting as opposed to a continuous fashion, with insulitis linked to hypoxia-regulated gene control and diabetes with C/EBP and Nkx2 gene control.

scholarly journals Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes

2002 ◽  
Vol 109 (1) ◽  
pp. 79-87 ◽  
Author(s):  
Marc S. Horwitz ◽  
Alex Ilic ◽  
Cody Fine ◽  
Enrique Rodriguez ◽  
Nora Sarvetnick
Keyword(s):  
T Cells ◽  
Autoimmune Diabetes ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Autoreactive T Cells

scholarly journals Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

2017 ◽  
Vol 25 (5) ◽  
pp. 1207 ◽  
Author(s):  
Shuhei Morita ◽  
S. Armando Villalta ◽  
Hannah C. Feldman ◽  
Ames C. Register ◽  
Wendy Rosenthal ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

2017 ◽  
Vol 25 (4) ◽  
pp. 883-897.e8 ◽  
Author(s):  
Shuhei Morita ◽  
S. Armando Villalta ◽  
Hannah C. Feldman ◽  
Ames C. Register ◽  
Wendy Rosenthal ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Β Cells ◽  
Pancreatic Β Cells

scholarly journals Syntaxin 4 enrichment in β-cells prevents conversion to autoimmune diabetes in non-obese diabetic (NOD) mice

Diabetes ◽  
2021 ◽  
pp. db210170
Author(s):  
Eunjin Oh ◽  
Erika M. McCown ◽  
Miwon Ahn ◽  
Pablo A. Garcia ◽  
Sergio Branciamore ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Syntaxin 4

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.

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