A Critical Role for Lymphotoxin-β Receptor in the Development of Diabetes in Nonobese Diabetic Mice

To assess the role of lymphotoxin-β receptor (LTβR) in diabetes pathogenesis, we expressed an LTβR–Fc fusion protein in nonobese diabetic (NOD) mice. The fusion protein was expressed in the embryo, reached high levels for the first 2 wk after birth, and then declined progressively with age. High expression of LTβR–Fc blocked diabetes development but not insulitis. After the decline in chimeric protein concentration, mice became diabetic with kinetics similar to the controls. Early expression of fusion protein resulted in disrupted splenic architecture. However, primary follicles and follicular dendritic cells, but not marginal zones, developed in aged mice. Hence, LTβR signaling is required for diabetes development and regulates follicular and marginal zone structures via qualitatively or quantitatively distinct mechanisms.

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Rotavirus Infection of Infant and Young Adult Nonobese Diabetic Mice Involves Extraintestinal Spread and Delays Diabetes Onset

Journal of Virology ◽

10.1128/jvi.00205-07 ◽

2007 ◽

Vol 81 (12) ◽

pp. 6446-6458 ◽

Cited By ~ 36

Author(s):

Kate L. Graham ◽

Joanne A. O'Donnell ◽

Yan Tan ◽

Natalie Sanders ◽

Emma M. Carrington ◽

...

Keyword(s):

Type 1 Diabetes ◽

Young Adult ◽

Infectious Virus ◽

Nod Mice ◽

Islet Autoimmunity ◽

Adult Mice ◽

Nonobese Diabetic ◽

Diabetes Development ◽

Nonobese Diabetic Mice

ABSTRACT Rotaviruses have been implicated as a possible viral trigger for exacerbations in islet autoimmunity, suggesting they might modulate type 1 diabetes development. In this study, the ability of rotavirus strain RRV to infect the pancreas and affect insulitis and diabetes was examined in nonobese diabetic (NOD) mice, an experimental model of type 1 diabetes. Mice were inoculated either orally or intraperitoneally as infants or young adults. In infant mice inoculated orally, rotavirus antigen was detected in pancreatic macrophages outside islets and infectious virus was found in blood cells, pancreas, spleen, and liver. Extraintestinal RRV spread and pancreatic presence of infectious virus also occurred in intraperitoneally inoculated infant and adult mice. The initiation of insulitis was unaltered by infection. The onset of diabetes was delayed in infant mice inoculated orally and infant and adult mice inoculated intraperitoneally. In contrast, adult mice inoculated orally showed no evidence of pancreatic RRV, the lowest rate of detectable RRV replication, and no diabetes modulation. Thus, the ability of RRV infection to modulate diabetes development in infant and young adult NOD mice was related to the overall extent of detectable virus replication and the presence of infectious virus extraintestinally, including in the pancreas. These studies show that RRV infection of infant and young adult NOD mice provides significant protection against diabetes. As these findings do not support the hypothesis that rotavirus triggers autoimmunity related to type 1 diabetes, further research is needed to resolve this issue.

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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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Potential immunomodulatory role of VIP in the implantation sites of prediabetic nonobese diabetic mice

Reproduction ◽

10.1530/rep-09-0171 ◽

2009 ◽

Vol 138 (4) ◽

pp. 733-742 ◽

Cited By ~ 16

Author(s):

Valeria Roca ◽

Mario Calafat ◽

Luciana Larocca ◽

Rosanna Ramhorst ◽

Mariana Farina ◽

...

Keyword(s):

Muscle Relaxation ◽

Embryo Implantation ◽

Nod Mice ◽

Exocrine Secretion ◽

Smooth Muscle Relaxation ◽

Nonobese Diabetic ◽

Cytokine Balance ◽

Implantation Sites ◽

Nonobese Diabetic Mice ◽

Allogeneic Response

Among several factors known to modulate embryo implantation and survival, uterine quiescence and neovascularization, maternal immunotolerance through the Th1/Th2 cytokine balance towards a Th2 profile, local regulatory T-cell (Treg) activation, and high levels of progesterone were assigned a prominent role. Vasoactive intestinal peptide (VIP) is a neuroimmunopeptide that has anti-inflammatory effects, promotes Th2 cytokines and CD4+CD25+FOXP3+Treg activation, and stimulates exocrine secretion, smooth muscle relaxation, and vasodilatation favoring uterus quiescence. The goal of the present work was to explore the participation of VIP in the implantation sites of normal and pregnant prediabetic nonobese diabetic (NOD) females, a mouse strain that spontaneously develops an autoimmune exocrinopathy similar to Sjögren's syndrome. Our results indicate a reduction in litter size from the third parturition onwards in the NOD female lifespan with increased resorption rates. Progesterone systemic levels were significantly decreased in pregnant NOD mice compared with BALB/c mice, although the allogeneic response to progesterone by spleen cells was not impaired. VIP receptors,Vipr1andVipr2(Vpac1andVpac2), were expressed at the implantation sites and VIP induced leukemia inhibitory factor (LIF) and Treg marker expression in both strains; however, a reducedVipexpression was found in NOD implantation sites. We conclude that the reduced birth rate at 16-week-old NOD mice with a Th1 systemic cytokine profile involves resorption processes with a lower expression of VIP at the sites of implantation, which acts as a local inducer of pro-implantatory LIF and Treg activation.

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I-E+ nonobese diabetic mice develop insulitis and diabetes.

Journal of Experimental Medicine ◽

10.1084/jem.178.3.793 ◽

1993 ◽

Vol 178 (3) ◽

pp. 793-803 ◽

Cited By ~ 96

Author(s):

P L Podolin ◽

A Pressey ◽

N H DeLarato ◽

P A Fischer ◽

L B Peterson ◽

...

Keyword(s):

Bone Marrow ◽

Mhc Class Ii ◽

Type I Diabetes ◽

Spontaneous Diabetes ◽

Nod Mice ◽

Large Degree ◽

Type I ◽

Congenic Strains ◽

Nonobese Diabetic ◽

Nonobese Diabetic Mice

The development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E+ or I-E- non-NOD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congenic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E+ NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E- F1 strains were no more protected from diabetes than I-E+ F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived cells, is not sufficient to provide protection from diabetes.

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Type-I Interferons Inhibit Interleukin-10 Signaling and Favor Type 1 Diabetes Development in Nonobese Diabetic Mice

Frontiers in Immunology ◽

10.3389/fimmu.2018.01565 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Marcos Iglesias ◽

Anirudh Arun ◽

Maria Chicco ◽

Brandon Lam ◽

C. Conover Talbot ◽

...

Keyword(s):

Type 1 Diabetes ◽

Interleukin 10 ◽

Type I Interferons ◽

Type I ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Diabetes Development ◽

Nonobese Diabetic Mice

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The postnatal maternal environment influences diabetes development in nonobese diabetic mice

Journal of Autoimmunity ◽

10.1016/j.jaut.2006.11.006 ◽

2007 ◽

Vol 28 (1) ◽

pp. 19-23 ◽

Cited By ~ 17

Author(s):

L.R. Washburn ◽

H. Dang ◽

J. Tian ◽

D.L. Kaufman

Keyword(s):

Diabetic Mice ◽

Maternal Environment ◽

Nonobese Diabetic ◽

Diabetes Development ◽

Nonobese Diabetic Mice

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Thymic negative selection is functional in NOD mice

Journal of Experimental Medicine ◽

10.1084/jem.20112593 ◽

2012 ◽

Vol 209 (3) ◽

pp. 623-637 ◽

Cited By ~ 29

Author(s):

Michael Mingueneau ◽

Wenyu Jiang ◽

Markus Feuerer ◽

Diane Mathis ◽

Christophe Benoist

Keyword(s):

Genetic Variation ◽

Negative Selection ◽

Biochemical Analysis ◽

Large Fraction ◽

Nod Mice ◽

Double Positive ◽

Clonal Deletion ◽

Nonobese Diabetic ◽

Early Expression ◽

Bone Marrow Chimeras

Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD αβ-TCR signalosomes. Therefore, NOD genetic variation influences αβ/γδ-lineage decisions when the αβ-TCR heterodimer is prematurely expressed, but not the process of negative selection.

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Pancreatic Lymph Nodes Are Required for Priming of β Cell Reactive T Cells in NOD Mice

Journal of Experimental Medicine ◽

10.1084/jem.20011353 ◽

2002 ◽

Vol 196 (3) ◽

pp. 369-377 ◽

Cited By ~ 190

Author(s):

Marie-Claude Gagnerault ◽

Jian Jian Luan ◽

Chantal Lotton ◽

Françoise Lepault

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Autoimmune Diabetes ◽

Adult Life ◽

Nod Mice ◽

Autoreactive T Cells ◽

Nonobese Diabetic ◽

Autoreactive T Cell ◽

Pancreatic Lymph Nodes ◽

Diabetes Development

Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that results from the destruction of insulin secreting β cells by diabetogenic T cells. The time and location of the encounter of autoantigen(s) by naive autoreactive T cells in normal NOD mice are still elusive. To address these issues, we analyzed diabetes development in mice whose spleen or pancreatic lymph nodes (panLNs) had been removed. Excision of panLNs (panLNx) at 3 wk protected mice against insulin autoantibodies (IAAs), insulitis, and diabetes development almost completely, but had no effect when performed at 10 wk. The protection afforded by panLNx at weaning was not due to modifications of the immune system, the absence of autoreactive T cells, or the increase in the potency of regulatory T cells. That panLNs are dispensable during adult life was confirmed by the capacity of 10-wk-old panLNx irradiated recipients to develop diabetes upon transfer of diabetogenic T cells. In contrast, splenectomy had no effect at any age. Partial excision of mesenteric LN at 3 wk did not prevent accelerated diabetes by cyclophosphamide as panLNx did. Thus, in normal NOD mice, autoreactive T cell initial priming occurs in LNs draining the target organ of the disease from 3 wk of age.

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