scholarly journals A Defect in Tryptophan Catabolism Impairs Tolerance in Nonobese Diabetic Mice

2003 ◽  
Vol 198 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Ursula Grohmann ◽  
Francesca Fallarino ◽  
Roberta Bianchi ◽  
Ciriana Orabona ◽  
Carmine Vacca ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cell Function ◽  
Nod Mice ◽  
Central Tolerance ◽  
Nonobese Diabetic ◽  
Tryptophan Catabolism ◽  
Ifn Γ ◽  
Nonobese Diabetic Mice ◽  
Antigen Presenting ◽  
Experimental Autoimmune

The predisposition of nonobese diabetic (NOD) mice to develop autoimmunity reflects deficiencies in both peripheral and central tolerance. Several defects have been described in these mice, among which aberrant antigen-presenting cell function and peroxynitrite formation. Prediabetes and diabetes in NOD mice have been targeted with different outcomes by a variety of immunotherapies, including interferon (IFN)-γ. This cytokine may be instrumental in specific forms of tolerance by virtue of its ability to activate immunosuppressive tryptophan catabolism. Here, we provide evidence that IFN-γ fails to induce tolerizing properties in dendritic cells from highly susceptible female mice early in prediabetes. This effect is associated with impaired tryptophan catabolism, is related to transient blockade of the Stat1 pathway of intracellular signaling by IFN-γ, and is caused by peroxynitrite production. However, the use of a peroxynitrite inhibitor can rescue tryptophan catabolism and tolerance in those mice. This is the first report of an experimental autoimmune disease in which defective tolerance is causally linked to impaired tryptophan catabolism.

scholarly journals CTLA-4–Ig Activates Forkhead Transcription Factors and Protects Dendritic Cells from Oxidative Stress in Nonobese Diabetic Mice

2004 ◽  
Vol 200 (8) ◽  
pp. 1051-1062 ◽  
Author(s):  
Francesca Fallarino ◽  
Roberta Bianchi ◽  
Ciriana Orabona ◽  
Carmine Vacca ◽  
Maria L. Belladonna ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Intracellular Signaling ◽  
Cytotoxic T Lymphocyte ◽  
Nod Mice ◽  
Soluble Form ◽  
Autocrine Signaling ◽  
Female Mice ◽  
Nonobese Diabetic ◽  
Tryptophan Catabolism ◽  
Ifn Γ

Prediabetes and diabetes in nonobese diabetic (NOD) mice have been targeted by a variety of immunotherapies, including the use of a soluble form of cytotoxic T lymphocyte antigen 4 (CTLA-4) and interferon (IFN)-γ. The cytokine, however, fails to activate tolerogenic properties in dendritic cells (DCs) from highly susceptible female mice early in prediabetes. The defect is characterized by impaired induction of immunosuppressive tryptophan catabolism, is related to transient blockade of the signal transducer and activator of transcription (STAT)1 pathway of intracellular signaling by IFN-γ, and is caused by peroxynitrite production. Here, we show that soluble CTLA-4 imparts suppressive properties to DCs from early prediabetic NOD female mice through mechanisms that rely on autocrine signaling by IFN-γ. Although phosphorylation of STAT1 in response to IFN-γ is compromised in those mice, CTLA-4 obviates the defect. IFN-γ–driven expression of tryptophan catabolism by CTLA-4–immunoglobulin is made possible through the concomitant activation of the Forkhead Box class O (FOXO) transcription factor FOXO3a, induction of the superoxide dismutase gene, and prevention of peroxynitrite formation.

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.

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 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 Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice

Diabetes ◽  
2006 ◽  
Vol 55 (7) ◽  
pp. 2098-2105 ◽  
Author(s):  
P. Alard ◽  
J. N. Manirarora ◽  
S. A. Parnell ◽  
J. L. Hudkins ◽  
S. L. Clark ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Function ◽  
Nod Mice ◽  
Antigen Presenting Cell ◽  
Diabetes Development ◽  
Antigen Presenting

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 TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

2011 ◽  
Vol 187 (4) ◽  
pp. 1702-1712 ◽  
Author(s):  
Jonathan Chee ◽  
Eveline Angstetra ◽  
Lina Mariana ◽  
Kate L. Graham ◽  
Emma M. Carrington ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Tnf Receptor ◽  
Diabetic Mice ◽  
Nonobese Diabetic ◽  
T Cell Function ◽  
Nonobese Diabetic Mice

scholarly journals The Role of Lymphocyte Subsets in Accelerated Diabetes in Nonobese Diabetic–Rat Insulin Promoter–B7-1 (NOD-RIP-B7-1) Mice

1998 ◽  
Vol 187 (12) ◽  
pp. 1985-1993 ◽  
Author(s):  
F. Susan Wong ◽  
Irene Visintin ◽  
Li Wen ◽  
Jennifer Granata ◽  
Richard Flavell ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
Nod Mice ◽  
Diabetic Rat ◽  
Nonobese Diabetic ◽  
Autoimmune Attack ◽  
Insulin Promoter ◽  
Onset Of Diabetes ◽  
Antigen Presenting

B7-1 transgene expression on the pancreatic islets in nonobese diabetic (NOD) mice leads to accelerated diabetes, with >50% of animals developing diabetes before 12 wk of age. The expression of B7-1 directly on the pancreatic β cells, which do not normally express costimulator molecules, converts the cells into effective antigen-presenting cells leading to an intensified autoimmune attack. The pancreatic islet infiltrate in diabetic mice consists of CD8 T cells, CD4 T cells, and B cells, similar to diabetic nontransgenic NOD mice. To elucidate the relative importance of each of the subsets of cells, the NOD–rat insulin promoter (RIP)-B7-1 animals were crossed with NOD.β2microglobulin −/− mice which lack major histocompatibility complex class I molecules and are deficient in peripheral CD8 T cells, NOD.CD4 −/− mice which lack T cells expressing CD4, and NOD.μMT −/− mice which lack B220-positive B cells. These experiments showed that both CD4 and CD8 T cells were necessary for the accelerated onset of diabetes, but that B cells, which are needed for diabetes to occur in normal NOD mice, are not required. It is possible that B lymphocytes play an important role in the provision of costimulation in NOD mice which is unnecessary in the NOD-RIP-B7-1 transgenic mice.

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