Genetic and pathogenic basis of autoimmune diabetes in NOD mice

doi:10.1016/0952-7915(94)90011-6

Current Opinion in Immunology

Volume 6, Issue 6, December 1994, Pages 900-906

https://doi.org/10.1016/0952-7915(94)90011-6 Get rights and content

Abstract

Non-obese diabetic (NOD) mice are an excellent model of T-cell mediated autoimmune insulin-dependent diabetes in humans. Recent studies in NOD mice have shown that this disease is a result of epistatic interactions between multiple genes, both inside and outside the major histocompatibility complex (MHC), generating T cells reactive against an expanding repertoire of autoantigens.

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Among NOD mice, induction of diabetes occurs preferentially in female animals as compared to their male counterparts. They exhibit mild ketosis, and their susceptibility to diabetes depends on an autoimmune reaction against the pancreas (Kataoka et al., 1983; Makino et al., 1980; Serreze and Leiter, 1994). Induction of diabetes is interfered by microbial contamination.
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Islet-reactive memory CD4⁺ T cells are an essential feature of type 1 diabetes (T1D) as they are involved in both spontaneous disease and in its recurrence after islet transplantation. Expansion and enrichment of memory T cells have also been shown in the peripheral blood of diabetic patients. Here, using high-throughput sequencing, we investigated the clonal diversity of the TCRβ repertoire of memory CD4⁺ T cells in the pancreatic lymph nodes (PaLN) of non-obese diabetic (NOD) mice and examined their clonal overlap with islet-infiltrating memory CD4 T cells. Both prediabetic and diabetic NOD mice exhibited a restricted TCRβ repertoire dominated by clones expressing TRBV13-2, TRBV13-1 or TRBV5 gene segments. There is a limited degree of TCRβ overlap between the memory CD4 repertoire of PaLN and pancreas as well as between the prediabetic and diabetic group. However, public TCRβ clonotypes were identified across several individual animals, some of them with sequences similar to the TCRs from the islet-reactive T cells suggesting their antigen-driven expansion. Moreover, the majority of the public clonotypes expressed TRBV13-2 (Vβ8.2) gene segment. Nasal vaccination with an immunodominat peptide derived from the TCR Vβ8.2 chain led to protection from diabetes, suggesting a critical role for Vβ8.2⁺ CD4⁺ memory T cells in T1D. These results suggest that memory CD4⁺ T cells bearing limited dominant TRBV genes contribute to the autoimmune diabetes and can be potentially targeted for intervention in diabetes. Furthermore, our results have important implications for the identification of public T cell clonotypes as potential novel targets for immune manipulation in human T1D.
Dietary polyherbal supplementation decreases CD3<sup>+</sup> cell infiltration into pancreatic islets and prevents hyperglycemia in nonobese diabetic mice
2015, Nutrition Research
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Thus, the consumption of polyherbal extracts preserved functional β-cell mass in NOD mice. Development of T1DM in NOD mice is known to be a T-lymphocyte–driven event [33,42]. Thus, we examined CD3+ (a T-lymphocyte marker) cell infiltration into pancreatic islets in both control and PHS fed animals.
Type 1 diabetes mellitus results from autoimmune-mediated destruction of pancreatic islet β-cells, a process associated with inflammatory signals. We hypothesized that dietary supplementation with botanicals known to contain anti-inflammatory properties would prevent losses in functional β-cell mass in nonobese diabetic (NOD) mice, a rodent model of autoimmune-mediated islet inflammation that spontaneously develops diabetes. Female NOD mice, a model of spontaneous autoimmune diabetes, were fed a diet supplemented with herbal extracts (1.916 g total botanical extracts per 1 kg of diet) over a 12-week period. The mice consumed isocaloric matched diets without (controls) and with polyherbal supplementation (PHS) ad libitum starting at a prediabetic stage (age 6 weeks) for 12 weeks. Control mice developed hyperglycemia (>180 mg/dL) within 16 weeks (n = 9). By contrast, mice receiving the PHS diet did not develop hyperglycemia by 18 weeks (n = 8). Insulin-positive cell mass within pancreatic islets was 31.9% greater in PHS mice relative to controls. We also detected a 26% decrease in CD3⁺ lymphocytic infiltration in PHS mice relative to mice consuming a control diet. In vitro assays revealed reduced β-cell expression of the chemokines CCL2 and CXCL10 after overnight PHS addition to the culture media. We conclude that dietary PHS delays initiation of autoimmune-mediated β-cell destruction and subsequent onset of diabetes mellitus by diminishing islet inflammatory responses.
Aire-dependent peripheral tissue antigen mRNAs in mTEC cells feature networking refractoriness to microRNA interaction
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The downregulation of PTA genes in mTECs is associated with the loss of self-tolerance, and the role of miRNAs in this process is not fully understood. Therefore, we studied the expression of mRNAs and miRNAs in mTECs from autoimmune NOD mice during the period when loss of self-tolerance occurs in parallel with non-autoimmune BALB/c mice. Although the expression of the transcriptional regulator Aire was unchanged, we observed downregulation of a set of PTA mRNAs. A set of miRNAs was also differentially expressed in these mice. The reconstruction of miRNA–mRNA interaction networks identified the controller miRNAs and predicted the PTA mRNA targets. Interestingly, the known Aire-dependent PTAs exhibited pronounced refractoriness in the networking interaction with miRNAs. This study reveals the existence of a new mechanism in mTECs, and this mechanism may have importance in the control of self-tolerance.
Cytokine production profiles in chronic relapsing-remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse
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In this context, chronic relapsing–remitting EAE (CREAE) is considered to be the most useful animal model for elucidating the pathophysiological mechanisms of MS. NOD mice naturally develop type 1 diabetes and are receptive to autoimmune disease induction [6]. In particular, this strain develops MS-like chronic relapsing–remitting demyelinating disease when administered a single dose of encephalitogenic MOG peptide 35–55 (MOG35–55).
Multiple sclerosis (MS) is a chronic demyelinating disease often displaying a relapsing–remitting course of neurological manifestations that is mimicked by experimental autoimmune encephalomyelitis (EAE) in animal models of MS. In particular, NOD mice immunized with myelin oligodendrocyte glycoprotein peptide 35–55 develop chronic relapsing–remitting EAE (CREAE). To elucidate the mechanisms that cause MS relapse, we investigated the histopathology and cytokine production of spleen cells and mRNA expression levels in the central nervous system (CNS) of CREAE mice. During the first attack, inflammatory cell infiltration around small vessels and in the subarachnoid space was observed in the spinal cord. Spleen cell production and mRNA expression in the CNS of several cytokines, including IFN-γ, TNF-α, IL-6, IL-17, and CC chemokine ligand 2 (CCL2), were higher in CREAE mice than in controls. Afterwards, parenchymal infiltration and demyelination were observed histologically in the spinal cord and corresponded with the more severe clinical symptoms of the first and second relapses. IL-17 and CCL2, but not IFN-γ, TNF-α, or IL-6, were also produced by spleen cells during recurrences. Our results suggested that the immune mechanisms in relapses were different from those in the first attack for CREAE. Further investigation of CREAE mechanisms may provide important insights into successful therapies for human relapsing–remitting MS.

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Genetic and pathogenic basis of autoimmune diabetes in NOD mice

Abstract

Adv Immunol

Nature

Diabetes

Nature

Immunopathogenesis of type 1 diabetes mellitus

T-cell clones from a type 1 diabetes patient respond to insulin secretory granule proteins

Nature

Antigen presenting cells and the immunogenetics of autoimmune diabetes in NOD mice

Regional Immunol

The effect of H-2 compatibility on pancreatic beta cell survival in the non-obese diabetic mouse

Transplantation

The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice

Autoimmune diabetes results from genetic defects manifest by antigen presenting cells

FASEB J

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

J Exp Med

Genetic control of diabetogenesis in NOD/Lt mice: development and analysis of congenic stocks

Diabetes

I-E+ nonobese diabetic mice develop insulitis and diabetes

J Exp Med

Defective activation of T suppressor cell function in non-obese diabetic mice. Potential relation to cytokine deficiencies

J Immunol

Prevention of diabetes in NOD mice by injection of autoreactive T lymphocytes

Diabetes

Suppression of diabetes mellitus in the non-obese diabetic (NOD) mouse by an autoreactive (anti-I-Ag7) islet-derived CD-4+ T-cell line

Diabetologia

Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hematopoietic origin, but not on thymic epithelium

J Immunol

The first external domain of the nonobese diabetic mouse class II I-Aβ chain is unique

A molecular basis for MHC class II-associated autoimmunity

Science

Self peptides isolated from MHC glycoproteins of non-obese diabetic mice

J Immunol

Major histocompatibility complex-linked diabetogenic gene of the nonobese diabetic mouse. Analysis of genomic DNA amplified by the polymerase chain reaction

J Clin Invest

Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α-chain

Nature

Prevention of diabetes in non-obese diabetic I-Ale transgenic mice

Nature

An Abd transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells

The effect of bone marrow and thymus chimerism between non-obese diabetic (NOD) and NOD-E transgenic mice, on the expression and prevention of diabetes

Eur J Immunol

Failure of a protective major histocompatibility complex class II molecule to delete autoreactive T cells in autoimmune diabetes

Linkage of faulty major histocompatibility complex class I to autoimmune diabetes

Science

Mechanisms of autoimmunity in type 1 diabetes

J Clin Immunol

Expression of intra-MHC transporter (Ham) genes in diabetes-susceptible NOD mice

Science

Polymorphism in mouse Tapl gene

J Immunol

Transporters from H-26, H-2d H-25, H-2k, and H287 (NOD/Lt) haplotype translocate similar sets of peptides

The role of CD4⁺ and CD8⁺ T cells in the destruction of islet grafts by spontaneously diabetic mice

Suppression of diabetes mellitus in the non-obese diabetic (NOD) mouse by an autoreactive (anti-I-A^g7) islet-derived CD-4⁺ T-cell line

An Ab^d transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells

Transporters from H-26, H-2^d H-25, H-2k, and H287 (NOD/Lt) haplotype translocate similar sets of peptides