Both TH1 and TH2 Cytokine mRNAs are Expressed in the NOD Mouse Pancreasin vivo

Faulkner-Jones, Beverly E.; Dempsey-Collier, Majella; Mandel, T. E.; Harrison, Leonard C.

doi:10.3109/08916939608995333

Cited by 17 publications

(9 citation statements)

References 25 publications

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“…High levels of these Th1-like cytokines after CY have also been demonstrated in control NOD mice in two independent studies [7,8,31]. Data on Th2 cytokines after CY are less concordant: Rothe et al found that IL-4 mRNA levels remained relatively constant after CY [7], while Faulkner-Jones et al described a rise in IL-4 mRNA levels [31]. In the present study we saw a diminished increase in Th1-like mRNA levels in 1,25(OH) 2 D 3 -treated NOD mice compared with controls after CY, but no significant differences in Th2-like cytokines after CY.…”

Section: Discussionmentioning

confidence: 83%

1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

Casteels¹,

Waer

Bouillon³

et al. 1998

Clinical and Experimental Immunology

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SUMMARYThe activated form of vitamin D, 1,25(OH) 2 D 3 , and its analogues can prevent type I diabetes in NOD mice. Protection is achieved without signs of systemic immunosuppression and is associated with a restoration of the defective immune regulator system of the NOD mice. The aim of the present study was to investigate whether this restoration of regulator cell function is the only mechanism in the prevention of diabetes by 1,25(OH) 2 D 3 . We tested therefore if 1,25(OH) 2 D 3 could prevent cyclophosphamideinduced diabetes, since diabetes occurring after cyclophosphamide injection is believed to be due to an elimination of suppresser cells. NOD mice treated with 1,25(OH) 2 D 3 (5 mg/kg every 2 days) from the time of weaning were clearly protected against diabetes induced by cyclophosphamide (200 mg/kg body wt at 70 days old) (2/12 (17%) versus 36/53 (68%) in control mice, P < 0·005). By co-transfer experiments it was demonstrated that cyclophosphamide had indeed eliminated the suppresser cells present in 1,25(OH) 2 D 3 -treated mice. Since cyclophosphamide injection did not break the protection offered by 1,25(OH) 2 D 3 , it was clear that diabetogenic effector cells were affected by 1,25(OH) 2 D 3 treatment as well. This was confirmed by the finding that splenocytes from 1,25(OH) 2 D 3 -treated mice were less capable of transferring diabetes in young, irradiated NOD mice, and by the demonstration of lower Th1 cytokine levels in the pancreases of 1,25(OH) 2 D 3 -treated, cyclophosphamide-injected mice. This better elimination of effector cells in 1,25(OH) 2 D 3 -treated mice could be explained by a restoration of the sensitivity to cyclophosphamide-induced apoptosis in both thymocytes and splenocytes, in normally apoptosis-resistant NOD mice. Altogether, these data indicate that the protection against diabetes offered by 1,25(OH) 2 D 3 may be independent of the presence of suppresser cells, and may involve increased apoptosis of Th1 autoimmune effector cells.

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Section: Discussionmentioning

confidence: 83%

1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

Casteels¹,

Waer

Bouillon³

et al. 1998

Clinical and Experimental Immunology

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“…An inherent dysregulation in Th1/Th2 cytokine production (Atkinson and Maclaren 1994;Beyhum et al 1997), as exemplified by altered production of and response to macrophage-and T-cell-derived cytokines, is associated with mouse models of type 1 diabetes (Faulkner-Jones et al 1996;Yoon et al 1998). Th1 cytokines, including IFN-γ and IL-2, induce islet β-cell destruction directly by activating CD8 + T cells, enhancing infiltration of these cells into the islets and releasing the synthesized cytotoxic mediators (Held et al 1990).…”

Section: Discussionmentioning

confidence: 99%

“…Immunological abnormalities observed in type 1 diabetes are characterized by the presence of autoreactive antibodies against β-cell constituents and other autoantigens (Hagopian et al 1993), circulating autoreactive T cells (Shimada et al 1996), highly expressed adhesion molecules on T cells (Itoh et al 1993;Martin et al 1996), reduced serum levels of cytokine inhibitors (MandrupPoulsen et al 1994), and sustained expression of cytokines and their high-affinity receptors (Hussain et al 1996;Kolb et al 1996;Stewart et al 1993). Among them, T-cell-and macrophage-derived cytokines, especially Th1 cytokines such as IFN-γ and IL-2, are considered to play important roles in the destruction of β cells (Faulkner-Jones et al 1996;Karlsson et al 2000;Karlsson and Ludvigsson 1998;Rapoport et al 1998;Yoon et al 1998). On the other hand, a Th2 cytokine, IL-10, was also reported to accelerate autoimmune destruction of β islet cells (Pakala et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel type 1 diabetes susceptibility gene, T-bet

et al. 2004

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The gene encoding interferon (IFN)-gamma, IFNG, is known as one of the candidate susceptibility genes for type 1 diabetes. In addition, cytokines, including IFN-gamma, play important roles in the pathogenesis of type 1 diabetes. Therefore, we focused on the Th1-specific T-box transcription factor gene (T-bet), which contributes to the induction of the hallmark Th1 cytokine, IFN-gamma. We first screened for polymorphisms in the T-bet gene and detected two microsatellite repeat polymorphisms located in intron 1 and the 3'- flanking region, and two single nucleotide polymorphisms, including a His33Gln substitution within the coding region. By association studies, the Gln-positive phenotype and (CA)14 allele in 3'-flanking region of T-bet were found to be associated with type 1 diabetes in the Japanese population. Furthermore, Gln33 T-bet showed a significantly higher transcriptional activity of the IFNG gene via a dual luciferase reporter assay. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the T-bet gene, and that variation in T-bet transcriptional activity may play a role in the development of type 1 diabetes, possibly through the effect on IFN-gamma production in Th1 cells.

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“…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%

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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Both T_H1 and T_H2 Cytokine mRNAs are Expressed in the NOD Mouse Pancreasin vivo

Cited by 17 publications

References 25 publications

1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in non-obese diabetic (NOD) mice and protects against diabetes

Identification of a novel type 1 diabetes susceptibility gene, T-bet

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

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