Androgen treatment prevents diabetes in nonobese diabetic mice.

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.

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Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice

Journal of Experimental Medicine ◽

10.1084/jem.186.7.989 ◽

1997 ◽

Vol 186 (7) ◽

pp. 989-997 ◽

Cited By ~ 160

Author(s):

David Kägi ◽

Bernhard Odermatt ◽

Peter Seiler ◽

Rolf M. Zinkernagel ◽

Tak W. Mak ◽

...

Keyword(s):

T Cells ◽

Autoimmune Diabetes ◽

Cytotoxic T Cells ◽

Disease Onset ◽

Spontaneous Diabetes ◽

Cell Loss ◽

Β Cell ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice ◽

Deficient Mice

To investigate the role of T cell–mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4+ and CD8+ T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for β cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic β cell loss by less efficient secondary effector mechanisms.

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

10.2337/figshare.16556424.v3 ◽

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.

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Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice.

Journal of Experimental Medicine ◽

10.1084/jem.179.4.1379 ◽

1994 ◽

Vol 179 (4) ◽

pp. 1379-1384 ◽

Cited By ~ 214

Author(s):

L Wogensen ◽

M S Lee ◽

N Sarvetnick

Keyword(s):

Islet Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Insulin Dependent Diabetes Mellitus ◽

Interleukin 10 ◽

Diabetic Mouse ◽

Dependent Diabetes Mellitus ◽

Beta Cell Destruction ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice

The T helper type 2 (Th2) cell product interleukin 10 (IL-10) inhibits the proliferation and function of Th1 lymphocytes and macrophages (M phi). The nonobese diabetic mouse strain (NOD/Shi) develops a M phi and T cell-dependent autoimmune diabetes that closely resembles human insulin-dependent diabetes mellitus (IDDM). The objective of the present study was to explore the consequences of localized production of IL-10 on diabetes development in NOD/Shi mice. Surprisingly, local production of IL-10 accelerated the onset and increased the prevalence of diabetes, since diabetes developed at 5-10 wk of age in 92% of IL-10 positive I-A beta g7/g7, I-E- mice in first (N2) and second (N3) generation backcrosses between IL-10 transgenic BALB/c mice and (NOD/Shi) mice. None of the IL-10 negative major histocompatibility complex-identical littermates were diabetic at this age. Furthermore, diabetes developed in 33% of I-A beta g7/d, I-E+ N3 mice in the presence of IL-10 before the mice were 10 wk old. Our findings support the notion that IL-10 should not simply be regarded as an immunoinhibitory cytokine, since it possesses powerful, immunostimulatory properties as well. Furthermore, our observations suggest that beta cell destruction in NOD mice may be a Th2-mediated event.

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Reovirus Delays Diabetes Onset but Does Not Prevent Insulitis in Nonobese Diabetic Mice

Journal of Virology ◽

10.1128/jvi.80.6.3078-3082.2006 ◽

2006 ◽

Vol 80 (6) ◽

pp. 3078-3082 ◽

Cited By ~ 12

Author(s):

J. Denise Wetzel ◽

Erik S. Barton ◽

James D. Chappell ◽

Geoffrey S. Baer ◽

Michelle Mochow-Grundy ◽

...

Keyword(s):

Pancreatic Islets ◽

Autoimmune Diabetes ◽

Primary Cultures ◽

Systemic Infection ◽

Nod Mice ◽

Β Cell ◽

Nonobese Diabetic ◽

Strain Type ◽

Nonobese Diabetic Mice ◽

Type 3

ABSTRACT Mice infected with reovirus develop abnormalities in glucose homeostasis. Reovirus strain type 3 Abney (T3A) was capable of systemic infection of nonobese diabetic (NOD) mice, an experimental model of autoimmune diabetes. Reovirus antigen was detected in pancreatic islets of T3A-infected mice, and primary cultures of pancreatic islets from NOD mice supported T3A growth. Significantly fewer T3A-infected animals compared to uninfected controls developed diabetes. However, despite the alteration in diabetes penetrance, insulitis was evident in T3A-infected mice. These results suggest that viral infection of NOD mice alters autoimmune responses to β-cell antigens and thereby delays development of diabetes.

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

10.2337/figshare.16556424 ◽

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.

Download Full-text

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

10.2337/figshare.16556424.v2 ◽

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.

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T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice.

Journal of Experimental Medicine ◽

10.1084/jem.169.5.1669 ◽

1989 ◽

Vol 169 (5) ◽

pp. 1669-1680 ◽

Cited By ~ 181

Author(s):

C Boitard ◽

R Yasunami ◽

M Dardenne ◽

J F Bach

Keyword(s):

T Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Insulin Dependent Diabetes Mellitus ◽

Lymphoid Cells ◽

Dependent Diabetes Mellitus ◽

Spleen Cells ◽

Nonobese Diabetic ◽

Insulin Dependent ◽

Onset Of Diabetes

The nonobese diabetic (NOD) mouse has recently been introduced as a model for insulin-dependent diabetes mellitus. The role of regulatory T cells in the development of antipancreatic autoimmunity in this model remains unclear. To evaluate the presence of suppressive phenomena, we used disease transfer by spleen cells from diabetic NOD mice into preirradiated adult recipients as a model for accelerated disease. Suppressor phenomena were detected by testing the protection afforded by lymphoid cells from nondiabetic NOD mice against diabetes transfer in irradiated recipients. Transfer of diabetes was delayed by reconstituting recipients with spleen cells from nondiabetic NOD donors. The greatest protection against diabetes transfer was conferred by spleen cells from 8-wk-old nondiabetic female NOD mice. Depletion experiments showed that the protection was dependent on CD4+ cells. Protection was also detected within thymic cells from nondiabetic NOD mice and protection conferred by spleen cells was abrogated by thymectomy of nondiabetic female, but not male, NOD donors at 3 wk of age. These findings indicate that suppressive CD4+ T cells that are dependent on the presence of the thymus may delay the onset of diabetes in female diabetes-prone NOD mice.

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Clostridial Butyrate Biosynthesis Enzymes Are Significantly Depleted in the Gut Microbiota of Nonobese Diabetic Mice

mSphere ◽

10.1128/msphere.00492-18 ◽

2018 ◽

Vol 3 (5) ◽

Cited By ~ 9

Author(s):

Alessandro Tanca ◽

Antonio Palomba ◽

Cristina Fraumene ◽

Valeria Manghina ◽

Michael Silverman ◽

...

Keyword(s):

Gut Microbiota ◽

Intestinal Microbiota ◽

Time Window ◽

High Resolution Mass Spectrometry ◽

Nod Mice ◽

16S Rrna Gene Sequencing ◽

Rrna Gene ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice

ABSTRACT Increasing evidence suggests that the intestinal microbiota is involved in the pathogenesis of type 1 diabetes (T1D). Here we sought to determine which gut microbial taxa and functions vary between nonobese diabetic (NOD) mice and genetically modified NOD mice protected from T1D (Eα16/NOD) at 10 weeks of age in the time window between insulitis development and T1D onset. The gut microbiota of NOD mice were investigated by analyzing stool samples with a metaproteogenomic approach, comprising both 16S rRNA gene sequencing and microbial proteome profiling through high-resolution mass spectrometry. A depletion of Firmicutes (particularly, several members of Lachnospiraceae) in the NOD gut microbiota was observed compared to the level in the Eα16/NOD mice microbiota. Moreover, the analysis of proteins actively produced by the gut microbiota revealed different profiles between NOD and Eα16/NOD mice, with the production of butyrate biosynthesis enzymes being significantly reduced in diabetic mice. Our results support a model for gut microbiota influence on T1D development involving bacterium-produced metabolites as butyrate. IMPORTANCE Alterations of the gut microbiota early in age have been hypothesized to impact T1D autoimmune pathogenesis. In the NOD mouse model, protection from T1D has been found to operate via modulation of the composition of the intestinal microbiota during a critical early window of ontogeny, although little is known about microbiota functions related to T1D development. Here, we show which gut microbial functions are specifically associated with protection from T1D in the time window between insulitis development and T1D onset. In particular, we describe that production of butyrate biosynthesis enzymes is significantly reduced in NOD mice, supporting the hypothesis that modulating the gut microbiota butyrate production may influence T1D development.

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