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 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 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>

scholarly journals Position β57 of I-Ag7 controls early anti-insulin responses in NOD mice, linking an MHC susceptibility allele to type 1 diabetes onset

2019 ◽  
Vol 4 (38) ◽  
pp. eaaw6329 ◽  
Author(s):  
Louis Gioia ◽  
Marie Holt ◽  
Anne Costanzo ◽  
Siddhartha Sharma ◽  
Brian Abe ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Disease Onset ◽  
Insulin Response ◽  
Nod Mice ◽  
Class Ii ◽  
Single Amino Acid ◽  
Specific Gene ◽  
Single Amino Acid Change

The class II region of the major histocompatibility complex (MHC) locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQβ chains supports this association; this single amino acid change influences how TCRs recognize peptides in the context of HLA-DQ8 and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin peptide MHC tetramers to examine CD4+ T cell responses to Ins12–20 and Ins13–21 peptides during the early prediabetic phase of disease in nonobese diabetic (NOD) mice. A single-cell analysis of anti-insulin CD4+ T cells performed in 6- and 12-week-old NOD mice revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans and produced either classical TH1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by T cells specific for Ins12–20, the register that supports a P9 switch mode of recognition. The presence of the P9 switch was demonstrated by TCR sequencing, reexpression, mutagenesis, and functional testing of TCRαβ pairs in vitro. Genetic correction of the I-Aβ57 mutation in NOD mice resulted in the disappearance of D/E residues in the CDR3β of anti-Ins12–20 T cells. These results provide a mechanistic molecular explanation that links the characteristic MHC class II polymorphism of T1D with the recognition of islet autoantigens and disease onset.

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.

scholarly journals Polysaccharide A-dependent opposing effects of mucosal and systemic exposures to human gut commensalBacteroides fragilisin type 1 diabetes

2018 ◽  
Author(s):  
M. Hanief. Sofi ◽  
Benjamin M. Johnson ◽  
Radhika R. Gudi ◽  
Amy Jolly ◽  
Marie-Claude Gaudreau ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Oral Administration ◽  
Disease Progression ◽  
Inflammatory Responses ◽  
Nod Mice ◽  
Gut Permeability ◽  
Opposing Effects ◽  
The Impact ◽  
Systemic Compartment

AbstractBacteroides fragilis(BF) is an integral component of the human colonic commensal microbiota. BF is also the most commonly isolated organism from clinical cases of intra-abdominal abscesses suggesting its potential to induce pro-inflammatory responses, upon accessing the systemic compartment. Hence, we examined the impact of mucosal and systemic exposures to BF on type 1 diabetes (T1D) incidence in non-obese diabetic (NOD) mice. The impact of intestinal exposure to BF under chemically-induced enhanced gut permeability condition, which permits microbial translocation, in T1D was also examined. While oral administration of pre-diabetic mice with heat-killed (HK) BF caused enhanced immune regulation and suppression of autoimmunity resulting in delayed hyperglycemia, mice that received HK BF by i.v. injection showed rapid disease progression. Importantly, polysaccharide-A deficient (ΔPSA) BF failed to produce these opposing effects upon oral and systemic deliveries. Further, BF induced modulation of disease progression was observed in WT, but not TLR2-deficient, NOD mice. Interestingly, oral administration of BF under enhanced gut permeability condition resulted in accelerated disease progression and rapid onset of hyperglycemia in NOD mice. Overall, these observations suggest that BF-like gut commensals can cause pro-inflammatory responses upon gaining access to systemic compartment and contribute to T1D in at-risk subjects.

scholarly journals Androgen treatment prevents diabetes in nonobese diabetic mice.

1992 ◽  
Vol 175 (5) ◽  
pp. 1409-1412 ◽  
Author(s):  
H S Fox
Keyword(s):  
Immune Cells ◽  
Autoimmune Diabetes ◽  
Disease Model ◽  
Disease Onset ◽  
Nod Mice ◽  
Model System ◽  
Androgen Treatment ◽  
Nonobese Diabetic ◽  
Islet Inflammation ◽  
Nonobese Diabetic Mice

The nonobese diabetic (NOD) mouse strain provides a model system for human autoimmune diabetes. This disease model is extensively used not only to examine the etiology and pathogenesis of diabetes, but also as a means to evaluate therapies. In NOD mice, the disease progresses from insulitis to islet destruction and clinical diabetes in a high percentage of female mice. In this study, androgen therapy, begun after the onset of insulitis, was found to prevent islet destruction and diabetes without eliminating the islet inflammation in female NOD mice. However, diabetes can be adoptively transferred into such hormone-treated recipients. The prevention of disease onset by androgen is likely due to the hormonal alteration of the development or function of the immune cells necessary for islet destruction.

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.

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 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.

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