scholarly journals Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5638-5646 ◽  
Author(s):  
Soojeong Kang ◽  
Eun-Jin Park ◽  
Yeonsoo Joe ◽  
Eunhui Seo ◽  
Mi-Kyoung Park ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Gelatin Zymography ◽  
Nod Mice ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Nonobese Diabetic ◽  
Induced Apoptosis

Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.

scholarly journals Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope

2011 ◽  
Vol 208 (7) ◽  
pp. 1501-1510 ◽  
Author(s):  
Carolin Daniel ◽  
Benno Weigmann ◽  
Roderick Bronson ◽  
Harald von Boehmer
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
Cell Clones ◽  
Autoimmune Attack ◽  
Agonistic Activity ◽  
Novel Strategy

Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic β cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-Ag7 molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3+ regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease.

scholarly journals Helminth Infection Can Reduce Insulitis and Type 1 Diabetes through CD25- and IL-10-Independent Mechanisms

2009 ◽  
Vol 77 (12) ◽  
pp. 5347-5358 ◽  
Author(s):  
Qian Liu ◽  
Krishnan Sundar ◽  
Pankaj K. Mishra ◽  
Gity Mousavi ◽  
Zhugong Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Helminth Infection ◽  
Inflammatory Responses ◽  
Nod Mice ◽  
Interleukin 4 ◽  
Heligmosomoides Polygyrus ◽  
Nonobese Diabetic

ABSTRACT Parasitic helminth infection has been shown to modulate pathological inflammatory responses in allergy and autoimmune disease. The aim of this study was to examine the effects of infection with a helminth parasite, Heligmosomoides polygyrus, on type 1 diabetes (T1D) in nonobese diabetic (NOD) mice and to elucidate the mechanisms involved in this protection. H. polygyrus inoculation at 5 weeks of age protected NOD mice from T1D until 40 weeks of age and also inhibited the more aggressive cyclophosphamide-induced T1D. Moreover, H. polygyrus inoculation as late as 12 weeks of age reduced the onset of T1D in NOD mice. Following H. polygyrus inoculation of NOD mice, pancreatic insulitis was markedly inhibited. Interleukin-4 (IL-4), IL-10, and IL-13 expression and the frequency of CD4+ CD25+ FoxP3+ regulatory T cells were elevated in mesenteric and pancreatic lymph nodes. Depletion of CD4+ CD25+ T cells in vivo did not abrogate H. polygyrus-induced T1D protection, nor did anti-IL-10 receptor blocking antibody. These findings suggest that infection with H. polygyrus significantly inhibits T1D in NOD mice through CD25- and IL-10-independent mechanisms and also reduces the severity of T1D when administered late after the onset of insulitis.

scholarly journals Correction to: In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice

Diabetologia ◽  
2019 ◽  
Vol 62 (8) ◽  
pp. 1517-1517
Author(s):  
Midhat H. Abdulreda ◽  
R. Damaris Molano ◽  
Gaetano Faleo ◽  
Maite Lopez-Cabezas ◽  
Alexander Shishido ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Vivo Imaging ◽  
Nod Mice

scholarly journals Rodent Models for Investigating the Dysregulation of Immune Responses in Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Feng-Cheng Chou ◽  
Heng-Yi Chen ◽  
Shyi-Jou Chen ◽  
Mei-Cho Fang ◽  
Huey-Kang Sytwu
Keyword(s):  
Type 1 Diabetes ◽  
Animal Studies ◽  
Genetic Manipulation ◽  
Nod Mice ◽  
Environmental Parameters ◽  
Conditional Knockout ◽  
Therapeutic Approaches ◽  
Nonobese Diabetic ◽  
Genetically Manipulated

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producingβcells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.

scholarly journals Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

PLoS Genetics ◽  
2019 ◽  
Vol 15 (6) ◽  
pp. e1008178 ◽  
Author(s):  
Jochen Mattner ◽  
Javid P. Mohammed ◽  
Michael E. Fusakio ◽  
Claudia Giessler ◽  
Carl-Philipp Hackstein ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Functional Data ◽  
Susceptibility Gene ◽  
Nod Mice ◽  
Nonobese Diabetic

scholarly journals Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Susanne W. Bruun ◽  
Knud Josefsen ◽  
Julia T. Tanassi ◽  
Aleš Marek ◽  
Martin H. F. Pedersen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cells ◽  
Degradation Products ◽  
Intestinal Barrier ◽  
Nod Mice ◽  
Radioactive Label ◽  
Nonobese Diabetic ◽  
Gliadin Peptide ◽  
Gliadin Peptides

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

scholarly journals In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice

Diabetologia ◽  
2019 ◽  
Vol 62 (7) ◽  
pp. 1237-1250 ◽  
Author(s):  
Midhat H. Abdulreda ◽  
R. Damaris Molano ◽  
Gaetano Faleo ◽  
Maite Lopez-Cabezas ◽  
Alexander Shishido ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Vivo Imaging ◽  
Nod Mice
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