scholarly journals IFN Regulatory Factors 4 and 8 Expression in the NOD Mouse

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Gilles Besin ◽  
Simon Gaudreau ◽  
Émilie Dumont-Blanchette ◽  
Michael Ménard ◽  
Chantal Guindi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Type 1 Diabetes ◽  
Nod Mice ◽  
Nod Mouse ◽  
Dc Functions ◽  
Gm Csf ◽  
Diabetes Progression ◽  
Islet Inflammation

Dendritic cells (DCs) contribute to islet inflammation and its progression to diabetes in NOD mouse model and human. DCs play a crucial role in the presentation of autoantigen and activation of diabetogenic T cells, and IRF4 and IRF8 are crucial genes involved in the development of DCs. We have therefore investigated the expression of these genes in splenic DCs during diabetes progression in NOD mice. We found that IRF4 expression was upregulated in splenocytes and in splenic CD11c+DCs of NOD mice as compared to BALB/c mice. In contrast, IRF8 gene expression was higher in splenocytes of NOD mice whereas its expression was similar in splenic CD11c+DCs of NOD and BALB/c mice. Importantly, levels of IRF4 and IRF8 expression were lower in tolerogenic bone marrow derived DCs (BMDCs) generated with GM-CSF as compared to immunogenic BMDCs generated with GM-CSF and IL-4. Analysis of splenic DCs subsets indicated that high expression of IRF4 was associated with increased levels of CD4+CD8α−IRF4+CD11c+DCs but not CD4−CD8α+IRF8+CD11c+DCs in NOD mice. Our results showed that IRF4 expression was up-regulated in NOD mice and correlated with the increased levels of CD4+CD8α−DCs, suggesting that IRF4 may be involved in abnormal DC functions in type 1 diabetes in NOD mice.

Proinsulin 2 Knockout NOD Mice: A Model for Genetic Variation of Insulin Gene Expression in Type 1 Diabetes

Diabetes ◽  
2002 ◽  
Vol 51 (Supplement 3) ◽  
pp. S489-S493 ◽  
Author(s):  
D. Dubois-Lafforgue ◽  
L. Mogenet ◽  
K. Thebault ◽  
J. Jami ◽  
P. Krief ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Genetic Variation ◽  
Nod Mice ◽  
Insulin Gene ◽  
Insulin Gene Expression

scholarly journals Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Xue-Song Zhang ◽  
Jackie Li ◽  
Kimberly A Krautkramer ◽  
Michelle Badri ◽  
Thomas Battaglia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Early Life ◽  
System Development ◽  
Nod Mice ◽  
Intestinal Microbiome ◽  
Host Immune System ◽  
Intestinal Immunity ◽  
Immune System Development

The early-life intestinal microbiota plays a key role in shaping host immune system development. We found that a single early-life antibiotic course (1PAT) accelerated type 1 diabetes (T1D) development in male NOD mice. The single course had deep and persistent effects on the intestinal microbiome, leading to altered cecal, hepatic, and serum metabolites. The exposure elicited sex-specific effects on chromatin states in the ileum and liver and perturbed ileal gene expression, altering normal maturational patterns. The global signature changes included specific genes controlling both innate and adaptive immunity. Microbiome analysis revealed four taxa each that potentially protect against or accelerate T1D onset, that were linked in a network model to specific differences in ileal gene expression. This simplified animal model reveals multiple potential pathways to understand pathogenesis by which early-life gut microbiome perturbations alter a global suite of intestinal responses, contributing to the accelerated and enhanced T1D development.

scholarly journals Adaptive Immunity and Pathogenesis of Diabetes: Insights Provided by the α4–Integrin Deficient NOD Mouse

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2597
Author(s):  
Salim Oulghazi ◽  
Sarah K. Wegner ◽  
Gabriele Spohn ◽  
Nina Müller ◽  
Sabine Harenkamp ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Islet Cell ◽  
Cell Injury ◽  
Nod Mice ◽  
Nod Mouse ◽  
Modest Contribution ◽  
Human Type 1 Diabetes

Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. Conclusion: α4 is a potential target for primary or secondary prevention of T1D.

scholarly journals Parabacteroides distasonis enhances Type 1 Diabetes autoimmunity via molecular mimicry

2020 ◽  
Author(s):  
Qian Huang ◽  
I-Ting Chow ◽  
Claudia Brady ◽  
Amol Raisingani ◽  
Danmeng Li ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Molecular Mimicry ◽  
Nod Mice ◽  
Cross Reactivity ◽  
Nod Mouse ◽  
Human Gut ◽  
Human T Cell

ABSTRACTType 1 Diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic β-cells. Focusing on the main insulin epitope, insulin B-chain 9-23 (insB:9-23), we explored whether a microbial insB:9-23 mimic could modulate T1D. We now demonstrate that a microbial insB:9-23 mimic of Parabacteroides distasonis, a human gut commensal, exclusively stimulates non-obese diabetic (NOD) mouse T cells specific to insB:9-23. Indeed, immunization of NOD mice with either the bacterial mimic peptide or insB:9-23 further verified the cross-reactivity in vivo. Modeling P. distasonis peptide revealed a potential pathogenic register 3 binding. P. distasonis colonization of the female NOD mice gut accelerated T1D onset. In addition, adoptive transfer of splenocytes from NOD mice colonized with P. distasonis to NOD.SCID recipients conferred the enhanced disease phenotype. Integration analysis of published infant T1D gut microbiome data revealed that P. distasonis peptide is not present in the gut microbiota in the first year of life of infants that eventually develop T1D. Furthermore, P. distasonis peptide can stimulate human T cell clones specific to insB:9-23 and T1D patients demonstrated a strong humoral immune response to P. distasonis than controls. Taken together, our studies define a potential molecular mimicry link between T1D pathogenesis and the gut microbiota.One Sentence SummaryThe human gut commensal bacterium, Parabacteroides distasonis, accelerates type 1 diabetes in the NOD mouse model of the disease and involves expression of an insulin B:9-23 epitope mimic, supporting a potential disease mechanism involving molecular mimicry.

scholarly journals Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Wenxian Fu ◽  
Julia Farache ◽  
Susan M Clardy ◽  
Kimie Hattori ◽  
Palwinder Mander ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Nod Mice ◽  
Β Cells ◽  
Β Cell ◽  
Multiple Cancer ◽  
Short Treatment ◽  
Islet Inflammation ◽  
Circulating T Cells ◽  
Epigenetic Modulation

Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a ‘combination therapy’ currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration.

scholarly journals Coxsackievirus B Vaccines Prevent Infection-Accelerated Diabetes in NOD Mice and Have No Disease-Inducing Effect

2021 ◽  
Author(s):  
Virginia M Stone ◽  
Marta Butrym ◽  
Minna M Hankaniemi ◽  
Amir-Babak Sioofy-Khojine ◽  
Vesa P Hytönen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Progression ◽  
Neutralizing Antibodies ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Disease Etiology ◽  
Established Disease ◽  
Islet Inflammation

Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including non-human primates. Before initiating clinical trials with this type of vaccine it was also important to address whether a) the vaccine itself induces adverse immune reactions including accelerating diabetes onset in a diabetes prone host and b) the vaccine can prevent CVB induced diabetes in a well-established disease model. Here we present results from studies in which female NOD mice were left untreated, mock-vaccinated or vaccinated with CVB1-6 vaccine and monitored for insulitis occurrence or diabetes development. We demonstrate that vaccination induces virus neutralizing antibodies without altering insulitis scores or the onset of diabetes. We also show that NOD mice vaccinated with a CVB1 vaccine are protected from CVB-induced accelerated disease onset. Taken together, these studies show that CVB vaccines do not alter islet inflammation or accelerate disease progression in an animal model that spontaneously develops autoimmune type 1 diabetes. However, they can prevent CVB-mediated disease progression in the same model. <b></b>

scholarly journals Chromogranin A Deficiency Confers Protection from Autoimmune Diabetes Via Multiple Mechanisms

2021 ◽  
Author(s):  
Virginia M Stone ◽  
Marta Butrym ◽  
Minna M Hankaniemi ◽  
Amir-Babak Sioofy-Khojine ◽  
Vesa P Hytönen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Disease Progression ◽  
Neutralizing Antibodies ◽  
Autoimmune Diabetes ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Disease Etiology ◽  
Islet Inflammation

Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including non-human primates. Before initiating clinical trials with this type of vaccine it was also important to address whether a) the vaccine itself induces adverse immune reactions including accelerating diabetes onset in a diabetes prone host and b) the vaccine can prevent CVB induced diabetes in a well-established disease model. Here we present results from studies in which female NOD mice were left untreated, mock-vaccinated or vaccinated with CVB1-6 vaccine and monitored for insulitis occurrence or diabetes development. We demonstrate that vaccination induces virus neutralizing antibodies without altering insulitis scores or the onset of diabetes. We also show that NOD mice vaccinated with a CVB1 vaccine are protected from CVB-induced accelerated disease onset. Taken together, these studies show that CVB vaccines do not alter islet inflammation or accelerate disease progression in an animal model that spontaneously develops autoimmune type 1 diabetes. However, they can prevent CVB-mediated disease progression in the same model. <b></b>

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.

scholarly journals Abnormal Cannabidiol protects pancreatic beta cells in mouse models of experimental Type 1 diabetes

2020 ◽  
Author(s):  
Isabel Gonzalez-Mariscal ◽  
Macarena Pozo Morales ◽  
Silvana Yanina Romero-Zerbo ◽  
Vanesa Espinosa-Jimenez ◽  
Alejandro Escamilla ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Lymph Nodes ◽  
Beta Cell ◽  
Mouse Models ◽  
Nod Mice ◽  
List Type ◽  
Pancreatic Lymph Nodes ◽  
Islet Inflammation

ABSTRACTBackground and PurposeThe atypical cannabinoid Abn-CBD was reported to improve the inflammatory status in preclinical models of several pathologies including autoimmune diseases. However, its potential for autoimmune diabetes, i.e. type 1 diabetes (T1D), is unknown.Experimental ApproachWe used two mouse models of T1D, streptozotocin (STZ)-injected and non-obese diabetic (NOD) mice. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1mg/kg of body weight) or vehicle for 1 week, following STZ treatment, and euthanized 1 week later. Six-week-old female NOD mice were treated with Abn-CBD (0.1-1mg/kg) or vehicle for 12 weeks and then euthanized. Blood, pancreas, pancreatic lymph nodes and circulating T cells were collected and processed for analysis. Glycemia was also monitored.Key ResultsAbn-CBD decreased circulating proinflammatory cytokines, ameliorated islet inflammation and the autoimmune attack, showing a 2-fold decrease in CD8+ T cells infiltration and reduced Th1/Th2 ratio in pancreatic lymph nodes of STZ-injected mice. Mechanistically, Abn-CBD reduced intra-islet phospho-NF-κB and TXNIP. Concomitant reduction of islet cell apoptosis and intra-islet fibrosis were observed in Abn-CBD pre-treated mice compared to vehicle. In NOD mice, Abn-CBD reduced the expression of Ifng, Il21, Tnfa and Il10 while increased Il4 in circulating CD4+ T cells compared to vehicle, reducing the severity of insulitis and improving glucose tolerance.Conclusion and ImplicationsAltogether, we found that Abn-CBD reduces intra-islet inflammation and delays the progression of insulitis in mouse models of T1D, preserving healthy functional islets. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat early stages of T1D.WHAT IS ALREADY KNOWN-Phytocannabinoids such as cannabidiol (CBD) have anti-inflammatory and glucose-lowering properties-The CBD derivative Abn-CBD ameliorates inflammation in various diseases and modulates beta cell functionWHAT THIS STUDY ADDS-Abn-CBD reduces systemic and pancreatic inflammation in mice models of type 1 diabetes-Abn-CBD prevents beta cell damage and loss during type 1 diabetes onsetCLINICAL SIGNIFICANCE-Synthetic cannabinoids emerge as potential treatment for type 1 diabetes

scholarly journals Gene Expression Analysis of the Pre-Diabetic Pancreas to Identify Pathogenic Mechanisms and Biomarkers of Type 1 Diabetes

2020 ◽  
Vol 11 ◽  
Author(s):  
Linda Yip ◽  
Rebecca Fuhlbrigge ◽  
Reem Alkhataybeh ◽  
C. Garrison Fathman
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Disease Progression ◽  
Expression Analysis ◽  
Peripheral Blood ◽  
Gene Expression Analysis ◽  
Nod Mice ◽  
Human Pancreas ◽  
Blood Samples

Type 1 Diabetes (T1D) occurs as a result of the autoimmune destruction of pancreatic β-cells by self-reactive T cells. The etiology of this disease is complex and difficult to study due to a lack of disease-relevant tissues from pre-diabetic individuals. In this study, we performed gene expression analysis on human pancreas tissues obtained from the Network of Pancreatic Organ Donors with Diabetes (nPOD), and showed that 155 genes were differentially expressed by ≥2-fold in the pancreata of autoantibody-positive (AA+) at-risk individuals compared to healthy controls. Only 48 of these genes remained changed by ≥2-fold in the pancreata of established T1D patients. Pathway analysis of these genes showed a significant association with various immune pathways. We were able to validate the differential expression of eight disease-relevant genes by QPCR analysis: A significant upregulation of CADM2, and downregulation of TRPM5, CRH, PDK4, ANGPL4, CLEC4D, RSG16, and FCGR2B was confirmed in the pancreata of AA+ individuals versus controls. Studies have already implicated FCGR2B in the pathogenesis of disease in non-obese diabetic (NOD) mice. Here we showed that CADM2, TRPM5, PDK4, and ANGPL4 were similarly changed in the pancreata of pre-diabetic 12-week-old NOD mice compared to NOD.B10 controls, suggesting a possible role for these genes in the pathogenesis of both T1D and NOD disease. The loss of the leukocyte-specific gene, FCGR2B, in the pancreata of AA+ individuals, is particularly interesting, as it may serve as a potential whole blood biomarker of disease progression. To test this, we quantified FCGR2B expression in peripheral blood samples of T1D patients, and AA+ and AA- first-degree relatives of T1D patients enrolled in the TrialNet Pathway to Prevention study. We showed that FCGR2B was significantly reduced in the peripheral blood of AA+ individuals compared to AA- controls. Together, these findings demonstrate that gene expression analysis of pancreatic tissue and peripheral blood samples can be used to identify disease-relevant genes and pathways and potential biomarkers of disease progression in T1D.

Sign in / Sign up

Export Citation Format

Share Document