288-OR: Myeloid-Specific Deletion of Alox15 Decreases Pancreatic Inflammation and Protects from Spontaneous Diabetes Development in Nonobese Diabetic (NOD) Mice

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 288-OR
Author(s):  
ANNIE PINEROS ◽  
ABHISHEK KULKARNI ◽  
KARA ORR ◽  
LINDSEY GLENN ◽  
CHRISTOPHER A. REISSAUS ◽  
...  
Keyword(s):  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Nonobese Diabetic ◽  
Diabetes Development ◽  
Specific Deletion

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

2002 ◽  
Vol 196 (3) ◽  
pp. 369-377 ◽  
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.

scholarly journals Minimal Impact of a De Novo-Expressed  -Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice

Diabetes ◽  
2007 ◽  
Vol 56 (4) ◽  
pp. 1059-1068 ◽  
Author(s):  
M. M. Martinic ◽  
A. E. Juedes ◽  
D. Bresson ◽  
D. Homann ◽  
K. Skak ◽  
...  
Keyword(s):  
De Novo ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Minimal Impact ◽  
Diabetes Development

scholarly journals IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Huang ◽  
Qiyuan Tan ◽  
Ningwen Tai ◽  
James Alexander Pearson ◽  
Yangyang Li ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Gut Microbiota ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

scholarly journals Requirement of Fas for the Development of Autoimmune Diabetes in Nonobese Diabetic Mice

1997 ◽  
Vol 186 (4) ◽  
pp. 613-618 ◽  
Author(s):  
Naoto Itoh ◽  
Akihisa Imagawa ◽  
Toshiaki Hanafusa ◽  
Masako Waguri ◽  
Koji Yamamoto ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Autoimmune Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
Β Cell ◽  
Cell Destruction ◽  
Nonobese Diabetic

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic β cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate β cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune β cell destruction leading to IDDM.

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 Distinct alterations of gut morphology and microbiota characterize accelerated diabetes onset in nonobese diabetic mice

2019 ◽  
Vol 295 (4) ◽  
pp. 969-980 ◽  
Author(s):  
Marie-Christine Simon ◽  
Anna Lena Reinbeck ◽  
Corinna Wessel ◽  
Julia Heindirk ◽  
Tomas Jelenik ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Nod Mice ◽  
Short Chain Fatty Acids ◽  
Oxidative Capacity ◽  
Lifestyle Changes ◽  
Gut Morphology ◽  
Microbiome Composition ◽  
Nonobese Diabetic ◽  
Diabetes Development

The rising prevalence of type 1 diabetes (T1D) over the past decades has been linked to lifestyle changes, but the underlying mechanisms are largely unknown. Recent findings point to gut-associated mechanisms in the control of T1D pathogenesis. In nonobese diabetic (NOD) mice, a model of T1D, diabetes development accelerates after deletion of the Toll-like receptor 4 (TLR4). We hypothesized that altered intestinal functions contribute to metabolic alterations, which favor accelerated diabetes development in TLR4-deficient (TLR4−/−) NOD mice. In 70–90-day-old normoglycemic (prediabetic) female NOD TLR4+/+ and NOD TLR4−/− mice, gut morphology and microbiome composition were analyzed. Parameters of lipid metabolism, glucose homeostasis, and mitochondrial respiratory activity were measured in vivo and ex vivo. Compared with NOD TLR4+/+ mice, NOD TLR4−/− animals showed lower muscle mass of the small intestine, higher abundance of Bacteroidetes, and lower Firmicutes in the large intestine, along with lower levels of circulating short-chain fatty acids (SCFA). These changes are associated with higher body weight, hyperlipidemia, and severe insulin and glucose intolerance, all occurring before the onset of diabetes. These mice also exhibited insulin resistance–related abnormalities of energy metabolism, such as lower total respiratory exchange rates and higher hepatic oxidative capacity. Distinct alterations of gut morphology and microbiota composition associated with reduction of circulating SCFA may contribute to metabolic disorders promoting the progression of insulin-deficient diabetes/T1D development.

Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of αβ-TCR+ and CD4+ cells negates the effect

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2577-2584 ◽  
Author(s):  
Suzanne T. Ildstad ◽  
Paula M. Chilton ◽  
Hong Xu ◽  
Michele A. Domenick ◽  
Mukunda B. Ray
Keyword(s):  
Nod Mice ◽  
Cell Receptor ◽  
Host Cells ◽  
Cd4 Cells ◽  
Costimulatory Blockade ◽  
Nonobese Diabetic ◽  
Total Body ◽  
Specific Deletion

AbstractBone marrow transplantation blocks diabetes pathogenesis and reverses autoimmunity in nonobese diabetic (NOD) mice. However, there is a greater barrier to engraftment in the context of autoimmunity. In the present study, we characterized which recipient cells influence engraftment in prediabetic NOD mice, with the goal to replace myelotoxic conditioning with antigen-specific deletion of reactive host cells. Preconditioning of NOD mice with anti-CD8 and anti-CD154 monoclonal antibodies (mAbs) synergistically enhanced engraftment and significantly reduced the minimum total body irradiation (TBI) dose for engraftment. Strikingly, preconditioning with anti-CD4 mAb significantly impaired engraftment, negating the beneficial effect of anti-CD8, and resulted in a requirement for more TBI-based conditioning compared with controls conditioned with TBI alone. Similarly, more TBI was required when anti–T-cell receptor β (TCRβ) mAb was administered as preconditioning. The addition of anti-CD152 to CD154 preconditioning abrogated the engraftment-enhancing effect of anti-CD154. Taken together, these data indicate a role for CD4+ regulatory T cells in vivo which require signaling via CD152 in the induction of chimerism and tolerance in NOD recipients. Notably, disease prevention and reversal of autoimmunity was absolutely correlated with the establishment of chimerism. These studies have important implications for the design of novel clinical approaches to treat type 1 diabetes.

scholarly journals Autoimmune syndromes in major histocompatibility complex (MHC) congenic strains of nonobese diabetic (NOD) mice. The NOD MHC is dominant for insulitis and cyclophosphamide-induced diabetes.

1992 ◽  
Vol 176 (1) ◽  
pp. 67-77 ◽  
Author(s):  
L S Wicker ◽  
M C Appel ◽  
F Dotta ◽  
A Pressey ◽  
B J Miller ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Autoimmune Diabetes ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Nod Mouse ◽  
Major Histocompatibility ◽  
Nonobese Diabetic ◽  
Histocompatibility Complex ◽  
Genes Encoding ◽  
Lymphocytic Infiltrates

The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by multiple genes. At least one diabetogenic gene is linked to the major histocompatibility complex (MHC) of the NOD and is most likely represented by the two genes encoding the alpha and beta chains of the unique NOD class II molecule. Three other diabetogenic loci have recently been identified in the NOD mouse and are located on chromosomes 1, 3, and 11. In addition to the autoimmune diabetes which is caused by destruction of the insulin-producing beta cells in the pancreas, other manifestations of autoimmunity are seen in the NOD mouse. These include mononuclear cell inflammation of the submandibular and lacrimal glands, as well as the presence of circulating autoantibodies. To determine the effect of the non-MHC diabetogenic genes on the development of autoimmunity, we constructed the NOD.B10-H-2b (NOD.H-2b) strain, which possesses the non-MHC diabetogenic genes from the NOD mouse, but derives its MHC from the C57BL/10 (B10) strain. The NOD.H-2b strain does not develop insulitis, cyclophosphamide-induced diabetes, or spontaneous diabetes. It does, however, develop extensive lymphocytic infiltrates in the pancreas and the submandibular glands that are primarily composed of Thy 1.2+ T cells and B220+ B cells. In addition, autoantibodies are present in NOD.H-2b mice which recognize the "polar antigen" on the insulin-secreting rat tumor line RINm38. These observations demonstrate that the non-MHC genes in the NOD strain, in the absence of the NOD MHC, significantly contribute to the development of autoimmunity. The contribution of a single dose of the NOD MHC to autoimmunity was assessed with a (NOD x NOD.H-2b)F1 cross. Although only approximately 3% of F1 females developed spontaneous diabetes, approximately 50% of both female and male F1 mice developed insulitis, and 25% of females and 17% of males became diabetic after treatment with cyclophosphamide. These data demonstrate that the MHC-linked diabetogenic genes of the NOD mouse are dominant with decreasing levels of penetrance for the following phenotypes: insulitis greater than cyclophosphamide-induced diabetes greater than spontaneous diabetes.

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

2007 ◽  
Vol 81 (12) ◽  
pp. 6446-6458 ◽  
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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