Inhibition of Autoimmune Type 1 Diabetes by Gastrointestinal Helminth Infection

ABSTRACT Gastrointestinal nematode infections are prevalent worldwide and are potent inducers of T helper 2 responses with the capacity to modulate the immune response to heterologous antigens. Parasitic helminth infection has even been shown to modulate the immune response associated with autoimmune diseases. Nonobese diabetic (NOD) mice provide a model for studying human autoimmune diabetes; as in humans, the development of diabetes in NOD mice has been linked to the loss of self-tolerance to beta cell autoantigens. Previous studies with the NOD mouse have shown that helminth and bacterial infection appears to inhibit type 1 diabetes by disrupting the pathways leading to the Th1-mediated destruction of insulin-producing beta cells. The aim of our study was to examine whether infection with the gastrointestinal helminths Trichinella spiralis or Heligmosomoides polygyrus could inhibit the development of autoimmune diabetes in NOD mice and to analyze the mechanisms involved in protection and the role of Th2 responses. Protection from diabetes was afforded by helminth infection, appeared to inhibit autoimmune diabetes by disrupting pathways leading to the destruction of beta cells, and was mediated by seemingly independent mechanisms depending on the parasite but which may be to be related to the capacity of the host to mount a Th2 response.

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Replacing murine insulin 1 with human insulin protects NOD mice from diabetes

10.1101/823393 ◽

2019 ◽

Author(s):

Colleen M. Elso ◽

Nicholas A. Scott ◽

Lina Mariana ◽

Emma I. Masterman ◽

Andrew P.R. Sutherland ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cells ◽

Mouse Models ◽

Human Insulin ◽

Murine Model ◽

Pancreatic Beta Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Human Type 1 Diabetes

AbstractType 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse model and the clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.

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Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?

Diabetes ◽

10.2337/db16-1551 ◽

2017 ◽

Vol 66 (6) ◽

pp. 1443-1452 ◽

Cited By ~ 24

Author(s):

Allison L. O’Kell ◽

Clive Wasserfall ◽

Brian Catchpole ◽

Lucy J. Davison ◽

Rebecka S. Hess ◽

...

Keyword(s):

Animal Model ◽

Type 1 Diabetes ◽

Autoimmune Diabetes ◽

Nod Mice

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Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

Journal of Diabetes Research ◽

10.1155/2016/2424306 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Susanne W. Bruun ◽

Knud Josefsen ◽

Julia T. Tanassi ◽

Aleš Marek ◽

Martin H. F. Pedersen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cells ◽

Degradation Products ◽

Intestinal Barrier ◽

Nod Mice ◽

Radioactive Label ◽

Nonobese Diabetic ◽

Gliadin Peptide ◽

Gliadin Peptides

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

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Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

10.1101/2020.02.06.937839 ◽

2020 ◽

Author(s):

Heejoo Kim ◽

Jelena Perovanovic ◽

Arvind Shakya ◽

Zuolian Shen ◽

Cody N. German ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Target Genes ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Cell Receptor ◽

Glucose Levels ◽

Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

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Knockout of the Amino Acid Transporter SLC6A19 and Autoimmune Diabetes Incidence in Female Non-Obese Diabetic (NOD) Mice

Metabolites ◽

10.3390/metabo11100665 ◽

2021 ◽

Vol 11 (10) ◽

pp. 665

Author(s):

Matthew F. Waters ◽

Viviane Delghingaro-Augusto ◽

Kiran Javed ◽

Jane E. Dahlstrom ◽

Gaetan Burgio ◽

...

Keyword(s):

Type 1 Diabetes ◽

Amino Acid ◽

Confidence Interval ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Amino Acid Transporter ◽

Diabetes Incidence ◽

Amino Acid Availability ◽

Acid Transporter

High protein feeding has been shown to accelerate the development of type 1 diabetes in female non-obese diabetic (NOD) mice. Here, we investigated whether reducing systemic amino acid availability via knockout of the Slc6a19 gene encoding the system B(0) neutral amino acid transporter AT1 would reduce the incidence or delay the onset of type 1 diabetes in female NOD mice. Slc6a19 gene deficient NOD mice were generated using the CRISPR-Cas9 system which resulted in marked aminoaciduria. The incidence of diabetes by week 30 was 59.5% (22/37) and 69.0% (20/29) in NOD.Slc6a19+/+ and NOD.Slc6a19−/− mice, respectively (hazard ratio 0.77, 95% confidence interval 0.41–1.42; Mantel-Cox log rank test: p = 0.37). The median survival time without diabetes was 28 and 25 weeks for NOD.Slc6a19+/+ and NOD.Slc6a19−/− mice, respectively (ratio 1.1, 95% confidence interval 0.6–2.0). Histological analysis did not show differences in islet number or the degree of insulitis between wild type and Slc6a19 deficient NOD mice. We conclude that Slc6a19 deficiency does not prevent or delay the development of type 1 diabetes in female NOD mice.

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11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration Into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice

Hormone and Metabolic Research ◽

10.1055/s-0043-112761 ◽

2017 ◽

Vol 49 (09) ◽

pp. 693-700 ◽

Cited By ~ 4

Author(s):

Ahmed Shehata ◽

Leticia Quintanilla-Fend ◽

Sabrina Bettio ◽

Zahra Kamyabi-Moghaddam ◽

Ursula Kohlhofer ◽

...

Keyword(s):

Animal Model ◽

Type 1 Diabetes ◽

Body Weight ◽

Pancreatic Islets ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Apoptotic Cells ◽

Boswellic Acid ◽

Human Type 1 Diabetes

Abstract11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that – similar to the model of MLD-STZ-diabetes – also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.

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Effective Destruction of Fas-deficient Insulin-producing β Cells in Type 1 Diabetes

Journal of Experimental Medicine ◽

10.1084/jem.20030698 ◽

2003 ◽

Vol 198 (7) ◽

pp. 1103-1106 ◽

Cited By ~ 52

Author(s):

Irina Apostolou ◽

Zhenyue Hao ◽

Klaus Rajewsky ◽

Harald von Boehmer

Keyword(s):

T Cells ◽

Cell Death ◽

Type 1 Diabetes ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Β Cells ◽

Β Cell ◽

Influenza Hemagglutinin ◽

Insulin Promoter

In type 1 diabetes, autoimmune T cells cause destruction of pancreatic β cells by largely unknown mechanism. Previous analyses have shown that β cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of β cell death in type 1 diabetes. To directly test this hypothesis, we have generated a β cell–specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4+ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of β cells is a dispensable mode of cell death in this disease.

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Peptidylarginine deiminase inhibition prevents diabetes development in NOD mice

10.2337/figshare.13221704 ◽

2020 ◽

Author(s):

Ada Admin ◽

Fernanda M. C. Sodré ◽

Samal Bissenova ◽

Ylke Bruggeman ◽

Ronak Tilvawala ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Autoimmune Diseases ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Effector Memory ◽

Cell Reactivity ◽

Diabetes Development ◽

T Cell Reactivity

Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate, characterized by reduced frequencies of effector memory CD4+ T cells and a modest reduction in the frequency of IFNγ-producing CD4+ and CD8+ T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes.

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Peripherally-induced regulatory T cells contribute to the control of autoimmune diabetes

10.1101/199646 ◽

2017 ◽

Cited By ~ 1

Author(s):

Cornelia Schuster ◽

Fangzhu Zhao ◽

Stephan Kissler

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Pancreatic Beta Cells ◽

Autoimmune Diabetes ◽

Nod Mice ◽

Beta Cell Autoimmunity ◽

Autoimmune Destruction ◽

Treg Function ◽

Distinct Role

AbstractType 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells and is partly caused by deficiencies in the Foxp3+ regulatory T cell (Treg) compartment. Conversely, therapies that increase Treg function can prevent autoimmune diabetes in animal models. The majority of Tregs develop in the thymus (tTregs), but a proportion of Foxp3+ Tregs is generated in the periphery (pTregs) from Foxp3-CD4+ T cell precursors. Whether pTregs play a distinct role in T1D has not yet been explored. We report here that pTregs are a key modifier of disease in the nonobesed diabetic (NOD) mouse model for T1D. We generated NOD mice deficient for the Foxp3 enhancer CNS1 involved in pTreg induction. We show that CNS1 knockout decreased the frequency of pTregs and increased the risk of diabetes. Our results show that pTregs fulfill an important non-redundant function in the prevention of beta cell autoimmunity that causes T1D.

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Commonality in the genetic control of Type 1 diabetes in humans and NOD mice: variants of genes in the IL-2 pathway are associated with autoimmune diabetes in both species

Biochemical Society Transactions ◽

10.1042/bst0360312 ◽

2008 ◽

Vol 36 (3) ◽

pp. 312-315 ◽

Cited By ~ 19

Author(s):

Dan B. Rainbow ◽

Laura Esposito ◽

Sarah K. Howlett ◽

Kara M. Hunter ◽

John A. Todd ◽

...

Keyword(s):

Type 1 Diabetes ◽

Disease Susceptibility ◽

Autoimmune Diabetes ◽

Interleukin 2 ◽

Nod Mice ◽

Common Disease ◽

Gene Products ◽

Specific Expression ◽

Allele Specific

Variants within the IL-2 (interleukin 2) and CD25 genes are associated with T1DM (Type 1 diabetes mellitus) in mice and humans respectively. Both gene products are essential for optimal immune tolerance and a partial failure to tolerize is linked to the autoimmune responses to insulin and other β-cell proteins that precede T1DM onset. Gene variants that contribute to common disease susceptibility often alter gene expression only modestly. Small expression changes can be technically challenging to measure robustly, especially since biological variation usually contributes negatively to this goal. The present review focuses on allele-specific expression assays that can be used to quantify genotype-determined expression differences such as those observed for IL-2, where the susceptibility allele is transcribed 2-fold less than the resistance allele.

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