On the various manifestations of spontaneous autoimmune diabetes in rodent models

Degermann, Sylvie; Reilly, Christina R.; Scott, Bernadette; Ogata, Lynn; Boehmer, Harald von; Lo, David

doi:10.1002/eji.1830241236

Cited by 56 publications

(45 citation statements)

References 30 publications

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“…To determine whether CD8 ϩ T cells in NOD mice undergo tolerance to a model pancreatic Ag, we produced NOD mice expressing the same InsHA transgene (NOD-InsHA). NOD-InsHA females develop spontaneous diabetes at a similar rate and incidence as normal NOD females (70% incidence by 28 wk of age) (28). Also, the level of HA expression on pancreatic ␤ cells is similar for NODInsHA and BALB-InsHA mice, as measured by flow cytometry using anti-HA Abs (data not shown).…”

Section: Ha-specific Cd8 ϩ T Cells Persist In Nod-inshamentioning

confidence: 70%

Defective CD8+ T Cell Peripheral Tolerance in Nonobese Diabetic Mice

Kreuwel

Biggs

Pilip

et al. 2001

The Journal of Immunology

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Nonobese diabetic (NOD) mice develop spontaneous autoimmune diabetes that involves participation of both CD4+ and CD8+ T cells. Previous studies have demonstrated spontaneous reactivity to self-Ags within the CD4+ T cell compartment in this strain. Whether CD8+ T cells in NOD mice achieve and maintain tolerance to self-Ags has not previously been evaluated. To investigate this issue, we have assessed the extent of tolerance to a model pancreatic Ag, the hemagglutinin (HA) molecule of influenza virus, that is transgenically expressed by pancreatic islet β cells in InsHA mice. Previous studies have demonstrated that BALB/c and B10.D2 mice that express this transgene exhibit tolerance of HA and retain only low-avidity CD8+ T cells specific for the dominant peptide epitope of HA. In this study, we present data that demonstrate a deficiency in peripheral tolerance within the CD8+ T cell repertoire of NOD-InsHA mice. CD8+ T cells can be obtained from NOD-InsHA mice that exhibit high avidity for HA, as measured by tetramer (KdHA) binding and dose titration analysis. Significantly, these autoreactive CD8+ T cells can cause diabetes very rapidly upon adoptive transfer into NOD-InsHA recipient mice. The data presented demonstrate a retention in the repertoire of CD8+ T cells with high avidity for islet Ags that could contribute to autoimmune diabetes in NOD mice.

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Section: Ha-specific Cd8 ϩ T Cells Persist In Nod-inshamentioning

confidence: 70%

Defective CD8+ T Cell Peripheral Tolerance in Nonobese Diabetic Mice

Kreuwel

Biggs

Pilip

et al. 2001

The Journal of Immunology

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“…1-3). The disparate effects of epithelial and dendritic cells have been attributed to differences in various cell surface molecules involved in cell-cell interactions, such as LFA-1͞ICAM-1 (23-25), CD28͞B7.1 (26,27), CD40͞gp39 (28,29), Fas͞FasL (30), and CD30͞CD30L (31). Experiments with knockout mice and specific inhibitors have suggested a role for these molecules in thymic selection, but also revealed that they are not always absolutely necessary (23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Differences in the level of expression of class I major histocompatibility complex proteins on thymic epithelial and dendritic cells influence the decision of immature thymocytes between positive and negative selection

Delaney

Sykulev

Eisen

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Both positive and negative selection of immature T cells rely on engagement of their antigen-specific receptors (TCR) by peptide in association with proteins encoded in the major histocompatibility complex (MHC) protein. The decision made between these two outcomes seems to be determined by the number of TCR engaged by peptide-MHC complexes. It has been unclear how such a mechanism can be reconciled with evidence that positive and negative selection occur in different thymic compartments and are mediated by different antigen-presenting cells (APCs). In this study we demonstrate that the level of class I MHC protein is 10-fold higher on thymic dendritic cells, which mediate the negative selection of immature T cells, than on thymic epithelial cells, which mediate for positive selection. We also demonstrate that as little as a 3-fold increase in the level of a particular cognate peptide-MHC ligand is sufficient to result in negative rather than positive selection. The results suggest that quantitative differences in the level of expression of class I MHC proteins on thymic epithelial and dendritic cells contribute to the opposing roles these cells play in forming the repertoire of mature class I MHC restricted (CD8 ؉ ) T cells.Studies of T cell development indicate that T cell maturation in the thymus is largely driven by the extent to which antigenspecific receptors (T cell receptors or TCR) on immature thymocytes are engaged by peptide-major histocompatibility complex (MHC) complexes on thymic antigen-presenting cells (APCs; ref. 1). When TCR interact with complexes that are present at relatively low levels, the corresponding thymocytes are stimulated to proceed along the maturation pathway (positive selection); if, however, the complexes are relatively abundant the thymocytes undergo cell death (negative selection). The thymic APCs also have been the subject of many studies. Most reports indicate that positive selection is promoted by thymic epithelial cells whereas negative selection is mediated largely by hemopoietic dendritic cells (DC; ref. 2). Studies of thymocyte maturation in the absence of thymic DC indicate that some T cells can be positively selected by the thymic epithelial cells even when they would otherwise be negatively selected by DC (3). In an attempt to understand the basis for the different outcomes mediated by thymic epithelial and dendritic cells, we used reaggregated thymic organ cultures to investigate cellular requirements for the selection of T cells that express the antigen-specific receptor (TCR) of the CD8 ϩ CTL clone known as 2C.The 2C (6), and the 2C CTL line was also found to recognize the p2Ca peptide in association with K b , albeit weakly (7,8). More recently another naturally processed peptide, EQYKFYSV (dEV8), that can be recognized weakly in association with K b by the 2C TCR has been identified (9).In this study we followed the transition of double-positive (CD4 ϩ , CD8

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“…The TCR-HA Tg Balb/c mice, expressing 14.3d TCR-HA recognizing the immunodominant CD4 T cell epitope of hemagglutinin (HA110-120) of A/PR/8/34 influenza virus in association with I-E d and Ins-HA Tg mice (B10.D2 mice), expressing the HA from the same virus in pancreatic β-cells under the rat insulin promoter were used [3,4]. Since the Ins-HA+/+ Tg mice were homozygous, and the TCR-HA+/-Tg mice were heterozigous, the offsprings were Ins-HA+/-, TCR-HA+/-dTg mice (which developed diabetes) or InsHA+/-, TCR-HA-/-single Tg mice (control group which did not develop diabetes) [5,6].…”

Section: Micementioning

confidence: 99%

Double transgenic mice with Type 1 diabetes mellitus develop somatic, metabolic and vascular disorders

Radu

Georgescu²,

Stăvaru

et al. 2004

J Cellular Molecular Medi

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The double transgenic mice (dTg) were obtained by mating: (i) transgenic mice expressing the hemagglutinin of influenza virus under the insulin promoter with (ii) transgenic mice expressing specific T lymphocytes with receptor for the immunodominant epitope of the same virus. In this study we show that dTg mice developed type 1 diabetes mellitus associated with hyperglycemia, low level of plasma insulin, glucosuria, weight loss and ~ 90% mortality (at 3 months biological age). The membrane of red blood cells was more sensitive to osmotic shock in diabetic mice, compared to non-diabetic mice, assessing systemic oxidative stress. Both vasoconstriction and vasorelaxation of the renal arteries decreased significantly in diabetic mice (compared to the control group of non-diabetic mice) related to the phenotypic change of endothelium and smooth muscle cells within the artery wall. This animal model, may be used in developing various strategies to study pancreatic β-cell function, as well as for a better metabolic control conducting to a reduced risk of vascular complications.

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On the various manifestations of spontaneous autoimmune diabetes in rodent models

Cited by 56 publications

References 30 publications

Defective CD8+ T Cell Peripheral Tolerance in Nonobese Diabetic Mice

Defective CD8+ T Cell Peripheral Tolerance in Nonobese Diabetic Mice

Differences in the level of expression of class I major histocompatibility complex proteins on thymic epithelial and dendritic cells influence the decision of immature thymocytes between positive and negative selection

Double transgenic mice with Type 1 diabetes mellitus develop somatic, metabolic and vascular disorders

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