CD4+ and CD8+ T lymphocytes: Clarification of their pathogenic roles in diabetes in the NOD mouse

Kay, Thomas W. H.; Chaplin, Helen; Parker, J.L.; Stephens, Leigh A.; Thomas, Helen E.

doi:10.1016/s0923-2494(97)87241-0

Cited by 38 publications

(32 citation statements)

References 63 publications

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“…IFN-g is a product of the Th1 subset of T lymphocytes, cells involved in cell-mediated immune responses and related to modulation of islet ß cell destruction (11,18,32). Indeed, previous studies showed that diabetes could be transferred to neonatal NOD mice, suggesting that both CD4+ and CD8+ are required for the initiation of insulitis, contributing to the development of diabetes (9,33). Furthermore, the morphological findings of the presence of macrophages in islet infiltrating cells suggest their participation in early events of the inflammatory reaction which lead to the recruitment of T cells (5).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in most NOD mouse colonies (8) a clear sexual dimorphism is present showing high incidence of diabetes among females (60-90%) and low incidence among males (10-20%). Both CD4+ and CD8+ T cell subsets are required for development of diabetes in NOD mice (9)(10)(11)(12). However, the precise mechanisms by which T cells destroy ß cells are unclear.…”

Section: Introductionmentioning

confidence: 99%

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Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

Ventura-Oliveira

Vilella

Zanin

et al. 2002

Braz J Med Biol Res

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Insulin-dependent diabetes mellitus is caused by autoimmune destruction of pancreatic ß cells. Non-obese diabetic (NOD) mice spontaneously develop diabetes similar to the human disease. Cytokines produced by islet-infiltrating mononuclear cells may be directly cytotoxic and can be involved in islet destruction coordinated by CD4+ and CD8+ cells. We utilized a semiquantitative RT-PCR assay to analyze in vitro the mRNA expression of TNF-a and IFN-g cytokine genes in isolated islets (N = 100) and spleen cells (5 x 10 5 cells) from female NOD mice during the development of diabetes and from female CBA-j mice as a related control strain that does not develop diabetes. Cytokine mRNAs were measured at 2, 4, 8, 14 and 28 weeks of age from the onset of insulitis to the development of overt diabetes. An increase in IFN-g expression in islets was observed for females aged 28 weeks (149 ± 29 arbitrary units (AU), P<0.05, Student t-test) with advanced destructive insulitis when compared with CBA-j mice, while TNF-a was expressed in both NOD and CBA-j female islets at the same level at all ages studied. In contrast, TNF-a in spleen was expressed at higher levels in NOD females at 14 weeks (99 ± 8 AU, P<0.05) and 28 weeks (144 ± 17 AU, P<0.05) of age when compared to CBA-j mice. The data suggest that IFN-g and TNF-a expression in pancreatic islets of female NOD mice is associated with ß cell destruction and overt diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

Ventura-Oliveira

Vilella

Zanin

et al. 2002

Braz J Med Biol Res

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“…1 While the immunological mechanisms responsible for this disease are not completely understood, self-reactive CD4 + and CD8 + T cells probably play a significant role in the damage that occurs to insulin-producing b-islet cells. [1][2][3] The prevalence of type 1 diabetes and other autoimmune diseases has increased dramatically over the past few decades. [4][5][6] An analysis of 37 epidemiological studies conducted from 1960 to 1996 reports that there has been an increase in the incidence of type 1 diabetes worldwide of 3% per year over that time period, and that by the year 2010 the incidence of type 1 diabetes may be as high as 50/100 000 persons in some developed countries.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3⁺ regulatory T cells

Hübner¹,

Mitre³

2009

Immunology

115

103

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Summary We sought to determine whether Litomosoides sigmodontis, a filarial infection of rodents, protects against type 1 diabetes in non‐obese diabetic (NOD) mice. Six‐week‐old NOD mice were sham‐infected or infected with either L3 larvae, adult male worms, or adult female worms. Whereas 82% of uninfected NOD mice developed diabetes by 25 weeks of age, no L. sigmodontis‐infected mice developed disease. Although all mice had evidence of ongoing islet cell inflammation by histology, L. sigmodontis‐infected mice had greater numbers of total islets and non‐infiltrated islets than control mice. Protection against diabetes was associated with a T helper type 2 (Th2) shift, as interleukin‐4 (IL‐4) and IL‐5 release from α‐CD3/α‐CD28‐stimulated splenocytes was greater in L. sigmodontis‐infected mice than in uninfected mice. Increased circulating levels of insulin‐specific immunoglobulin G1, showed that this Th2 shift occurs in response to one of the main autoantigens in diabetes. Multicolour flow cytometry studies demonstrated that protection against diabetes in L. sigmodontis‐infected NOD mice was associated with significantly increased numbers of splenic CD4+ CD25+ FoxP3+ regulatory T cells. Interestingly, injection of crude worm antigen into NOD mice also resulted in protection against type 1 diabetes, though to a lesser degree than infection with live L. sigmodontis worms. In conclusion, these studies demonstrate that filarial worms can protect against the onset of type 1 diabetes in NOD mice. This protection is associated with a Th2 shift, as demonstrated by cytokine and antibody production, and with an increase in CD4+ CD25+ FoxP3+ regulatory T cells.

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“…S tudies in the NOD mouse model of type 1 diabetes demonstrate that autoreactive T cells are responsible for the destruction of insulin-secreting pancreatic ␤ cells (1,2). In common with humans at risk for type 1 diabetes, NOD mice exhibit spontaneous immunity to insulin (3).…”

mentioning

confidence: 99%

Intranasal Vaccination with Proinsulin DNA Induces Regulatory CD4+ T Cells That Prevent Experimental Autoimmune Diabetes

Every

Kramer

Mannering

et al. 2006

The Journal of Immunology

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Insulin, an autoantigen in type 1 diabetes, when administered mucosally to diabetes-prone NOD mice induces regulatory T cells (Treg) that protect against diabetes. Compared with protein, Ag encoded as DNA has potential advantages as a therapeutic agent. We found that intranasal vaccination of NOD mice with plasmid DNA encoding mouse proinsulin II-induced CD4+ Treg that suppressed diabetes development, both after adoptive cotransfer with “diabetogenic” spleen cells and after transfer into NOD mice given cyclophosphamide to accelerate diabetes onset. In contrast to prototypic CD4+CD25+ Treg, CD4+ Treg induced by proinsulin DNA were both CD25+ and CD25− and not defined by markers such as glucocorticoid-induced TNFR-related protein (GITR), CD103, or Foxp3. Intriguingly, despite induction of Treg and reduced islet inflammation, diabetes incidence in proinsulin DNA-treated mice was unchanged. However, diabetes was prevented when DNA vaccination was performed under the cover of CD40 ligand blockade, known to prevent priming of CTL by mucosal Ag. Thus, intranasal vaccination with proinsulin DNA has therapeutic potential to prevent diabetes, as demonstrated by induction of protective Treg, but further modifications are required to improve its efficacy, which could be compromised by concomitant induction of pathogenic immunity.

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CD4+ and CD8+ T lymphocytes: Clarification of their pathogenic roles in diabetes in the NOD mouse

Cited by 38 publications

References 63 publications

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3⁺ regulatory T cells

Intranasal Vaccination with Proinsulin DNA Induces Regulatory CD4+ T Cells That Prevent Experimental Autoimmune Diabetes

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CD4+ and CD8+ T lymphocytes: Clarification of their pathogenic roles in diabetes in the NOD mouse

Cited by 38 publications

References 63 publications

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells

Intranasal Vaccination with Proinsulin DNA Induces Regulatory CD4+ T Cells That Prevent Experimental Autoimmune Diabetes

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Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3⁺ regulatory T cells