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

Reproduction ◽  
2009 ◽  
Vol 138 (4) ◽  
pp. 733-742 ◽  
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.

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

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
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.

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

1993 ◽  
Vol 178 (3) ◽  
pp. 793-803 ◽  
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.

scholarly journals Characterization of Type I Interferon-Associated Chemokines and Cytokines in Lacrimal Glands of Nonobese Diabetic Mice

2021 ◽  
Vol 22 (7) ◽  
pp. 3767
Author(s):  
Merri-Grace Allred ◽  
Michael S. Chimenti ◽  
Ashley E. Ciecko ◽  
Yi-Guang Chen ◽  
Scott M. Lieberman
Keyword(s):  
T Cells ◽  
Lacrimal Gland ◽  
Nod Mice ◽  
Type I Interferons ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Lacrimal Glands ◽  
Nonobese Diabetic ◽  
Nonobese Diabetic Mice

Type I interferons (IFNs) are required for spontaneous lacrimal gland inflammation in the nonobese diabetic (NOD) mouse model of Sjögren’s disease, but the consequences of type I IFN signaling are not well-defined. Here, we use RNA sequencing to define cytokine and chemokine genes upregulated in lacrimal glands of NOD mice in a type I IFN-dependent manner. Interleukin (IL)-21 was the highest differentially expressed cytokine gene, and Il21 knockout NOD mice were relatively protected from lacrimal gland inflammation. We defined a set of chemokines upregulated early in disease including Cxcl9 and Cxcl10, which share a receptor, CXCR3. CXCR3+ T cells were enriched in lacrimal glands with a dominant proportion of CXCR3+ regulatory T cells. Together these data define the early cytokine and chemokine signals associated with type I IFN-signaling in the development of lacrimal gland inflammation in NOD mice providing insight into the role of type I IFN in autoimmunity development.

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

2001 ◽  
Vol 193 (11) ◽  
pp. 1333-1340 ◽  
Author(s):  
Rachel Ettinger ◽  
Sibyl H. Munson ◽  
Cheng-Chi Chao ◽  
Mary Vadeboncoeur ◽  
Jon Toma ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Critical Role ◽  
Chimeric Protein ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
Early Expression ◽  
Diabetes Development ◽  
Β Receptor ◽  
Nonobese Diabetic Mice ◽  
Marginal Zones

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.

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 Resistance alleles at two non-major histocompatibility complex-linked insulin-dependent diabetes loci on chromosome 3, Idd3 and Idd10, protect nonobese diabetic mice from diabetes.

1994 ◽  
Vol 180 (5) ◽  
pp. 1705-1713 ◽  
Author(s):  
L S Wicker ◽  
J A Todd ◽  
J B Prins ◽  
P L Podolin ◽  
R J Renjilian ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nod Mice ◽  
Insulin Dependent Diabetes ◽  
Chromosome 3 ◽  
Major Histocompatibility ◽  
Congenic Strains ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex ◽  
Insulin Dependent ◽  
Nonobese Diabetic Mice

Development of diabetes in NOD mice is polygenic and dependent on both major histocompatibility complex (MHC)-linked and non-MHC-linked insulin-dependent diabetes (Idd) genes. In (F1 x NOD) backcross analyses using the B10.H-2g7 or B6.PL-Thy1a strains as the outcross partner, we previously identified several non-MHC Idd loci, including two located on chromosome 3 (Idd3 and Idd10). In the current study, we report that protection from diabetes is observed in NOD congenic strains having B6.PL-Thy1a- or B10-derived alleles at Idd3 or Idd10. It is important to note that only partial protection is provided by two doses of the resistance allele at either Idd3 or Idd10. However, nearly complete protection from diabetes is achieved when resistance alleles are expressed at both loci. Development of these congenic strains has allowed Idd3 to be localized between Glut2 and D3Mit6, close to the Il2 locus.

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

1994 ◽  
Vol 179 (4) ◽  
pp. 1379-1384 ◽  
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.

scholarly journals Toward Testing the Hypothesis that Group B Coxsackieviruses (CVB) Trigger Insulin-Dependent Diabetes: Inoculating Nonobese Diabetic Mice with CVB Markedly Lowers Diabetes Incidence

2002 ◽  
Vol 76 (23) ◽  
pp. 12097-12111 ◽  
Author(s):  
S. Tracy ◽  
K. M. Drescher ◽  
N. M. Chapman ◽  
K.-S. Kim ◽  
S. D. Carson ◽  
...  
Keyword(s):  
Viral Infections ◽  
Human Genetics ◽  
Nod Mice ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diabetes Incidence ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
Insulin Dependent ◽  
Group B ◽  
Nonobese Diabetic Mice

ABSTRACT Insulin-dependent (type 1) diabetes mellitus (T1D) onset is mediated by individual human genetics as well as undefined environmental influences such as viral infections. The group B coxsackieviruses (CVB) are commonly named as putative T1D-inducing agents. We studied CVB replication in nonobese diabetic (NOD) mice to assess how infection by diverse CVB strains affected T1D incidence in a model of human T1D. Inoculation of 4- or 8-week-old NOD mice with any of nine different CVB strains significantly reduced the incidence of T1D by 2- to 10-fold over a 10-month period relative to T1D incidences in mock-infected control mice. Greater protection was conferred by more-pathogenic CVB strains relative to less-virulent or avirulent strains. Two CVB3 strains were employed to further explore the relationship of CVB virulence phenotypes to T1D onset and incidence: a pathogenic strain (CVB3/M) and a nonvirulent strain (CVB3/GA). CVB3/M replicated to four- to fivefold-higher titers than CVB3/GA in the pancreas and induced widespread pancreatitis, whereas CVB3/GA induced no pancreatitis. Apoptotic nuclei were detected by TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay in CVB3/M-infected pancreata but not in CVB3/GA-infected pancreata. In situ hybridization detected CVB3 RNA in acinar tissue but not in pancreatic islets. Although islets demonstrated inflammatory infiltrates in CVB3-protected mice, insulin remained detectable by immunohistochemistry in these islets but not in those from diabetic mice. Enzyme-linked immunosorbent assay-based examination of murine sera for immunoglobulin G1 (IgG1) and IgG2a immunoreactivity against diabetic autoantigens insulin and HSP60 revealed no statistically significant relationship between CVB3-protected mice or diabetic mice and specific autoimmunity. However, when pooled sera from CVB3/M-protected mice were used to probe a Western blot of pancreatic proteins, numerous proteins were detected, whereas only one band was detected by sera from CVB3/GA-protected mice. No proteins were detected by sera from diabetic or normal mice. Cumulatively, these data do not support the hypothesis that CVB are causative agents of T1D. To the contrary, CVB infections provide significant protection from T1D onset in NOD mice. Possible mechanisms by which this virus-induced protection may occur are discussed.

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

2006 ◽  
Vol 80 (6) ◽  
pp. 3078-3082 ◽  
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.

scholarly journals The IL-1βReceptor Antagonist SER140 Postpones the Onset of Diabetes in Female Nonobese Diabetic Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Helena Cucak ◽  
Gitte Hansen ◽  
Niels Vrang ◽  
Torben Skarsfeldt ◽  
Eva Steiness ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Function ◽  
Interleukin 1 ◽  
Nod Mice ◽  
Small Peptide ◽  
Nonobese Diabetic ◽  
Onset Of Diabetes ◽  
Diabetes Progression ◽  
Nonobese Diabetic Mice

The cytokine interleukin-1β(IL-1β) is known to stimulate proinflammatory immune responses and impairβ-cell function and viability, all critical events in the pathogenesis of type 1 diabetes (T1D). Here we evaluate the effect of SER140, a small peptide IL-1βreceptor antagonist, on diabetes progression and cellular pancreatic changes in female nonobese diabetic (NOD) mice. Eight weeks of treatment with SER140 reduced the incidence of diabetes by more than 50% compared with vehicle, decreased blood glucose, and increased plasma insulin. Additionally, SER140 changed the endocrine and immune cells dynamics in the NOD mouse pancreas. Together, the data suggest that SER140 treatment postpones the onset of diabetes in female NOD mice by interfering with IL-1βactivated pathways.

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