scholarly journals Gene Transfection and Expression of Transforming Growth Factor-β1 in Nonobese Diabetic Mouse Islets Protects β-Cells in Syngeneic Islet Grafts from Autoimmune Destruction

2002 ◽  
Vol 11 (6) ◽  
pp. 519-528 ◽  
Author(s):  
Wilma L. Suarez-Pinzon ◽  
Yvonne Marcoux ◽  
Aziz Ghahary ◽  
Alex Rabinovitch
Keyword(s):  
Transforming Growth Factor ◽  
Islet Cells ◽  
Gene Transfection ◽  
Nod Mice ◽  
Nod Mouse ◽  
Β Cells ◽  
Nonobese Diabetic ◽  
Autoimmune Destruction ◽  
Mouse Islets ◽  
Tgf Β1

Nonobese diabetic (NOD) mice develop diabetes and destroy syngeneic islet grafts through an autoimmune response. Because transforming growth factor (TGF)-β1 downregulates immune responses, we tested whether overexpression of TGF-β1 by gene transfection of NOD mouse islets could protect β-cells in islet grafts from autoimmune destruction. NOD mouse islet cells were transfected with an adenoviral DNA expression vector encoding porcine latent TGF-β1 (Ad TGF- β1) or the adenoviral vector alone (control Ad vector). The frequency of total islet cells expressing TGF-1 protein was increased from 12±1% in control Ad vector-transfected cells to 89 ± 4% in Ad TGF-β1-transfected islet cells, and the frequency of β-cells that expressed TGF-β1 was increased from 12 ± 1% to 60 ± 7%. Also, secretion of TGF-β1 was significantly increased in islets that overexpressed TGF-β1. Ad TGF-β1-transfected NOD mouse islets that overexpressed TGF-β1 prevented diabetes recurrence after transplantation into diabetic NOD mice for a median of 22 days compared with only 7 days for control Ad vector-transfected islets (p = 0.001). Immunohistochemical examination of the islet grafts revealed significantly more TGF-β1+ cells and insulin+ cells and significantly fewer CD45+ leukocytes in Ad TGF-β1-transfected islet grafts. Also, islet β-cell apoptosis was significantly decreased whereas apoptosis of graft-infiltrating leukocytes was significantly increased in Ad TGF-β1-transfected islet grafts. These observations demonstrate that overexpression of TGF-β1, by gene transfection of NOD mouse islets, protects islet β-cells from apoptosis and autoimmune destruction and delays diabetes recurrence after islet transplantation.

scholarly journals Reversal of autoimmunity by mixed chimerism enables reactivation of β cells and transdifferentiation of α cells in diabetic NOD mice

2020 ◽  
Vol 117 (49) ◽  
pp. 31219-31230
Author(s):  
Shanshan Tang ◽  
Mingfeng Zhang ◽  
Samuel Zeng ◽  
Yaxun Huang ◽  
Melissa Qin ◽  
...  
Keyword(s):  
Nod Mice ◽  
Lineage Tracing ◽  
Mixed Chimerism ◽  
Cell Regeneration ◽  
Β Cells ◽  
Β Cell ◽  
Nonobese Diabetic ◽  
Autoimmune Destruction ◽  
Epidermal Growth

Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ductal progenitors, Nestin+mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

2013 ◽  
Vol 126 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Abhirup Jayasimhan ◽  
Kristy P. Mansour ◽  
Robyn M. Slattery
Keyword(s):  
Type 1 Diabetes ◽  
Cell Mass ◽  
Nod Mice ◽  
Diabetic Mouse ◽  
Nod Mouse ◽  
Β Cells ◽  
Autoimmune Destruction ◽  
Immune Mediated ◽  
And Function

T1D (Type 1 diabetes) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Studies in T1D patients have been limited by the availability of pancreatic samples, a protracted pre-diabetic phase and limitations in markers that reflect β-cell mass and function. The NOD (non-obese diabetic) mouse is currently the best available animal model of T1D, since it develops disease spontaneously and shares many genetic and immunopathogenic features with human T1D. Consequently, the NOD mouse has been extensively studied and has made a tremendous contribution to our understanding of human T1D. The present review summarizes the key lessons from NOD mouse studies concerning the genetic susceptibility, aetiology and immunopathogenic mechanisms that contribute to autoimmune destruction of β-cells. Finally, we summarize the potential and limitations of immunotherapeutic strategies, successful in NOD mice, now being trialled in T1D patients and individuals at risk of developing T1D.

scholarly journals Normal Incidence of Diabetes in NOD Mice Tolerant to Glutamic Acid Decarboxylase

2003 ◽  
Vol 197 (12) ◽  
pp. 1635-1644 ◽  
Author(s):  
Elmar Jaeckel ◽  
Ludger Klein ◽  
Natalia Martin-Orozco ◽  
Harald von Boehmer
Keyword(s):  
Glutamic Acid ◽  
Glutamic Acid Decarboxylase ◽  
Tolerance Induction ◽  
Nod Mice ◽  
Normal Incidence ◽  
Invariant Chain ◽  
Acid Decarboxylase ◽  
Β Cells ◽  
Nonobese Diabetic ◽  
Specific Tolerance

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in β cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.

SYNERGISTIC ALLO- AND AUTOIMMUNE DESTRUCTION OF MAJOR AND MINOR HISTOINCOMPATIBLE ISLET TRANSPLANTS IN THE NONOBESE DIABETIC (NOD) MICE.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S374
Author(s):  
Teru Okitsu ◽  
Alan C. Farney ◽  
Gregg Hadley ◽  
Stephen T. Bartlett
Keyword(s):  
Nod Mice ◽  
Nonobese Diabetic ◽  
Autoimmune Destruction ◽  
Islet Transplants

scholarly journals Development of Spontaneous Autoimmune Peripheral Polyneuropathy in B7-2–Deficient Nod Mice

2001 ◽  
Vol 194 (5) ◽  
pp. 677-684 ◽  
Author(s):  
Benoît Salomon ◽  
Lesley Rhee ◽  
Helene Bour-Jordan ◽  
Honor Hsin ◽  
Anthony Montag ◽  
...  
Keyword(s):  
T Cells ◽  
Nervous System ◽  
Autoimmune Diabetes ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Nod Mice ◽  
Nod Mouse ◽  
Nerve Tissue ◽  
Nonobese Diabetic ◽  
Peripheral Polyneuropathy

An increasing number of studies have documented the central role of T cell costimulation in autoimmunity. Here we show that the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, deficient in B7-2 costimulation, is protected from diabetes but develops a spontaneous autoimmune peripheral polyneuropathy. All the female and one third of the male mice exhibited limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves beginning at 20 wk of age. No central nervous system lesions were apparent. The peripheral nerve tissue was infiltrated with dendritic cells, CD4+, and CD8+ T cells. Finally, CD4+ T cells isolated from affected animals induced the disease in NOD.SCID mice. Thus, the B7-2–deficient NOD mouse constitutes the first model of a spontaneous autoimmune disease of the peripheral nervous system, which has many similarities to the human disease, chronic inflammatory demyelinating polyneuropathy (CIDP). This model demonstrates that NOD mice have “cryptic” autoimmune defects that can polarize toward the nervous tissue after the selective disruption of CD28/B7-2 costimulatory pathway.

scholarly journals Expression of somatostatin receptor subtypes 1–5 in pancreatic islets of normoglycaemic and diabetic NOD mice

2005 ◽  
Vol 153 (3) ◽  
pp. 445-454 ◽  
Author(s):  
E Ludvigsen ◽  
M Stridsberg ◽  
E T Janson ◽  
S Sandler
Keyword(s):  
Pancreatic Islets ◽  
Islet Cells ◽  
Somatostatin Receptor ◽  
Nod Mice ◽  
Receptor Subtypes ◽  
Β Cells ◽  
Somatostatin Receptor Subtypes ◽  
Icr Mouse ◽  
The Difference ◽  
Cell Expression

Objective: Somatostatin acts on five specific receptors (sst1–5) to elicit different biological functions. The non-obese diabetic (NOD) mouse is an experimental model of type 1 diabetes. The aim of this study was to investigate whether the islet expression of sst1–5 is affected during the development of diabetes in NOD mice, with insulitis accompanied by spontaneous hyperglycaemia. Methods: By immunostaining for sst1–5 the expression and co-expression together with the four major islet hormones in pancreatic islets were investigated in female and male NOD mice at different stages of disease. The NOD related non-diabetic ICR mouse was also examined. Results: The islet cells of diabetic NOD mice showed an increased islet cell expression of sst2–5 compared with normoglycaemic female NOD mice. This correlated to increasing age and extent of insulitis. Major findings from the co-expression investigations were that sst2 was expressed in a majority of β-cells in the normoglycaemic NOD mice, but absent in the β-cells in the diabetic NOD mice. A majority of the α-cells expressed sst2 and 5 in normoglycaemic and diabetic NOD mice. About 60% of δ-cells showed co-expression of sst4 and 5 in both normoglycaemic and diabetic NOD mice. 60% of pancreatic polypeptide (PP)-cells expressed sst4 in both groups. Insulitis was found to be accompanied by a down-regulation of sst in normoglycaemic animals. Conclusions: The difference in sst expression in the islets cells of diabetic mice may suggest either a contributing factor in the process leading to diabetes, or a defence response against ongoing β-cell destruction.

Detection of endogenous retrovirus antigens in NOD mouse pancreatic β-cells

1998 ◽  
Vol 32 (1) ◽  
pp. 86-94 ◽  
Author(s):  
H. Tsumura ◽  
M. Miyazawa ◽  
S. Ogawa ◽  
J. Z. Wang ◽  
Y. Ito ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Envelope Protein ◽  
Nod Mice ◽  
Protein S ◽  
Endogenous Retrovirus ◽  
Nod Mouse ◽  
Antisense Oligodeoxynucleotide ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Gag Protein

We characterized C-type retroviruses expressed in the pancreatic β-cells of non-obese diabetic (NOD) mice by immunohistochemical techniques and by inhibiting the production of viral particles using antisense oligonucleotides. Some cells in the pancreatic islets from both NOD and diabetes-resistant NOD-related mice (NON) reacted with a monoclonal antibody directed against the envelope protein(s) of polytropic viruses. On the other hand, NOD islet cells also showed strong immunoreactivity with an anti- gag protein monoclonal antibody and another anti-envelope protein(s) monoclonal antibody that is specific for xenotropic viruses. In antisense oligodeoxynucleotide inhibition assays, a xenotropic virus-specific phosphorothionate antisense oligodeoxynucleotide significantly inhibited the occurrence of C-type virus particles in NOD mouse islet β-cells. Therefore, C-type retrovirus-like particles expressed in NOD mouse pancreatic β-cells were considered to be endogenous xenotropic virus. The expression of the xenotropic viral genome may be involved in the pathogenesis of the diabetic syndrome in NOD mice.

scholarly journals Reversal of New-Onset Diabetes through Modulating Inflammation and Stimulating β-Cell Replication in Nonobese Diabetic Mice by a Dipeptidyl Peptidase IV Inhibitor

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3049-3060 ◽  
Author(s):  
Lei Tian ◽  
Jie Gao ◽  
Jianqiang Hao ◽  
Yu Zhang ◽  
Huimin Yi ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nod Mice ◽  
Cell Replication ◽  
Β Cell ◽  
Nonobese Diabetic ◽  
Onset Diabetes ◽  
Dpp Iv ◽  
Tgf Β1 ◽  
New Onset

Inhibition of dipeptidyl peptidase IV (DPP-IV) activity by NVP-DPP728, a DPP-IV inhibitor, improves the therapeutic efficacy of glucagon-like peptide-1 (GLP-1). CD26 is a membrane-associated glycoprotein with DPP-IV activity and is expressed on lymphocytes. We investigated the effect of NVP-DPP728 on reversing new-onset diabetes in nonobese diabetic (NOD) mice and modulating the inflammatory response and stimulating β-cell regeneration. New-onset diabetic NOD mice were treated with NVP-DPP728 for 2, 4, and 6 wk. Blood glucose level was monitored. Regulatory T cells in thymus and secondary lymph nodes, TGF-β1 and GLP-1 in plasma, and the insulin content in the pancreas were measured. Immunostaining for insulin and bromodeoxyuridine (BrdU) were performed. The correlation of β-cell replication with inflammation was determined. In NVP-DPP728-treated NOD mice, diabetes could be reversed in 57, 74, and 73% of mice after 2, 4, and 6 wk treatment, respectively. Insulitis was reduced and the percentage of CD4+CD25+FoxP3+ regulatory T cells was increased in treated NOD mice with remission. Plasma TGF-β1 and GLP-1, the insulin content, and both insulin+ and BrdU+ β-cells in pancreas were also significantly increased. No significant correlations were found between numbers of both insulin+ and BrdU+ β-cells in islets and β-cell area or islets with different insulitis score in NOD mice with remission of diabetes. In conclusion, NVP-DPP728 treatment can reverse new-onset diabetes in NOD mice by reducing insulitis, increasing CD4+CD25+FoxP3+ regulatory T cells, and stimulating β-cell replication. β-Cell replication is not associated with the degree of inflammation in NVP-DPP728-treated NOD mice.

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