THE NOD MOUSE: A Model of Immune Dysregulation

Anderson, Mark S.; Bluestone, Jeffrey A.

doi:10.1146/annurev.immunol.23.021704.115643

Cited by 954 publications

(1,039 citation statements)

References 232 publications

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“…Studies on B10 cells and mouse models of diabetes are limited to the nonobese diabetic (NOD) mouse, a spontaneous model of type 1 diabetes in which autoimmune destruction of the insulin-producing pancreatic β cells is primarily T cell mediated [90]. Although B cells clearly have a pathogenic role in disease initiation [91], B cells activated in vitro can maintain tolerance and transfer protection from type 1 diabetes in NOD mice [92,93].…”

Section: B10 Cells In Mouse Models Of Autoimmune Diseasementioning

confidence: 99%

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

2013

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B cell abnormalities contribute to the development and progress of autoimmune disease. Traditionally, the role of B cells in autoimmune disease was thought to be predominantly limited to the production of autoantibodies. Nevertheless, in addition to autoantibody production, B cells have other functions potentially relevant to autoimmunity. Such functions include antigen presentation to and activation of T cells, expression of co-stimulatory molecules and cytokine production. Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged. A variety of cytokines produced by regulatory B cell subsets have been reported, with IL-10 being the most studied. In this review, this specific IL-10-producing subset of regulatory B cells has been labeled B10 cells to highlight that the regulatory function of these rare B cells is mediated by IL-10, and to distinguish them from other B cell subsets that regulate immune responses through different mechanisms. B10 cells are a functionally defined subset currently identified only by their competency to produce and secrete IL-10 following appropriate stimulation. Although B10 cells share surface markers with other previously defined B cell subsets, currently there is no cell surface or intracellular phenotypic marker or set of markers unique to B10 cells. The recent discovery of an effective way to expand B10 cells ex vivo opens new horizons in the potential therapeutic applications of this rare B cell subset. This review highlights the current knowledge on B10 cells and discusses their potential as novel therapeutic agents in autoimmunity.

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Section: B10 Cells In Mouse Models Of Autoimmune Diseasementioning

confidence: 99%

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

2013

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“…NOD mice have a defect in thymic negative selection of self-reactive thymocytes that results in loss of tolerance to autoantigens [21]. In addition, NOD mice generate low numbers of regulatory T cells [22] and the suppressive effect of these cells decreases in an age-dependent manner [23].…”

Section: Gal-9 Treatment Does Not Induce An Active Tolerance In Nod Micementioning

confidence: 99%

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

2009

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Galectin-9 (gal-9), widely expressed in many tissues, regulates Th1 cells and induces their apoptosis through its receptor, T-cell Ig mucin 3, which is mainly expressed on terminally differentiated Th1 cells. Type 1 diabetes is a Th1-dominant autoimmune disease that specifically destroys insulin-producing b cells. To suppress the Th1 immune response in the development of autoimmune diabetes, we overexpressed gal-9 in NOD mice by injection of a plasmid encoding gal-9. Mice treated with gal-9 plasmid were significantly protected from diabetes and showed less severe insulitis compared with controls. Flow cytometric analyses in NOD-T1/2 double transgenic mice showed that Th1-cell population in spleen, pancreatic lymph node and pancreas was markedly decreased in gal-9 plasmidtreated mice, indicating a negative regulatory role of gal-9 in the development of pathogenic Th1 cells. Splenocytes from gal-9 plasmid-treated mice were less responsive to mitogenic stimulation than splenocytes from the control group. However, adoptive transfer of splenocytes from gal-9-treated or control mice caused diabetes in NOD/SCID recipients with similar kinetics, suggesting that gal-9 treatment does not induce active tolerance in NOD mice. We conclude that gal-9 may downregulate Th1 immune response in NOD mice and could be used as a therapeutic target in autoimmune diabetes.Key words: Galectin-9 . Th1 . T-cell Ig mucin 3 . Type 1 diabetes IntroductionWhen CD4 1 Th cells interact with class II MHC-peptide complex and costimulatory molecules on APC, they differentiate into several effector subsets. There are two major Th subsets that have unique patterns of cytokine secretion and different functional properties. Th1 cells produce cytokines such as IFN-g, IL-2, TNF-a and lymphotoxin that are commonly associated with cellmediated immune responses against intracellular pathogens, delayed-type hypersensitivity and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines such as IL-4, IL-5, IL-10 and IL-13 that are crucial for controlling extracellular helminth infections and promoting atopic and allergic diseases [1,2].Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease that selectively destroys the insulin-producing b cells in the pancreas. NOD mice spontaneously develop autoimmune diabetes with immunopathological features resembling those of human disease and can be used as an animal model to study the pathogenesis of T1D. Previous studies have demonstrated that transfer of NOD CD4 1 T cells to immunodeficient NOD/SCID mice can induce diabetes in those recipients, indicating that CD4 1 T cells play an important role in the pathogenesis of diabetes [3,4] [12]. Previous approaches using TIM-3-Ig fusion protein to interrupt the interactions between TIM-3 and its ligand in vivo resulted in hyperproliferation of Th1 cells and release of Th1-related cytokines [13]. TIM-3 ligand was subsequently identified as galectin-9 (gal-9) [14], a b-galactoside binding lectin that belongs to a growing family of animal lectins, the...

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“…Type 1 diabetes is the result of an immune-mediated destruction of insulin-producing beta cells in the pancreas, predominantly by cytotoxic T lymphocytes (CTLs) [15]. The primary activation of diabetogenic CTLs occurs within the pancreatic and gut-associated lymph nodes (LNs) [16,17].…”

Section: Introductionmentioning

confidence: 99%

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

et al. 2009

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Aims/hypothesis Increased exposure to enteric microbes as a result of intestinal barrier disruption is thought to contribute to the development of several intestinal inflammatory diseases; however, it less clear whether such exposure modulates the development of extra-intestinal inflammatory and autoimmune diseases. The goal of this study was to examine the potential role of pathogenic enteric microbes and intestinal barrier dysfunction in the pathogenesis of type 1 diabetes. Methods Using NOD mice, we assessed: (1) intrinsic barrier function in mice at different ages by measuring serum levels of FITC-labelled dextran; and (2) the impact on insulitis development of infection by strains of an enteric bacterial pathogen (Citrobacter rodentium) either capable (wild-type) or incapable (lacking Escherichia coli secreted protein F virulence factor owing to deletion of the gene [ΔespF]) of causing intestinal epithelial barrier disruption. Results Here we demonstrate that prediabetic (12-weekold) NOD mice display increased intestinal permeability compared with non-obese diabetes-resistant and C57BL/6 mice. We also found that young (4-week-old) NOD mice infected with wild-type C. rodentium exhibited accelerated development of insulitis in concert with infection-induced barrier disruption. In contrast, insulitis development was not altered in NOD mice infected with the non-barrier-disrupting ΔespF strain. Moreover, C. rodentium-infected NOD mice demonstrated increased activation and proliferation of pancreatic-draining lymph node T cells, including diabetogenic CD8 + T cells, compared with uninfected NOD mice. Conclusions/interpretation This is the first demonstration that a loss of intestinal barrier integrity caused by an enteric bacterial pathogen results in the activation of diabetogenic CD8 + T cells and modulates insulitis.

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THE NOD MOUSE: A Model of Immune Dysregulation

Cited by 954 publications

References 232 publications

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

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