Low Dose Poly I:C Prevents Diabetes in the Diabetes Prone BB Rat

Sobel, Douglas O.; Goyal, Deepshika; Ahvazi, Behrouz; Yoon, Ji‐Won; Chung, Young Hwa; Bagg, Adam; Harlan, David M.

doi:10.1006/jaut.1998.0203

Cited by 59 publications

(44 citation statements)

References 48 publications

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“…Poly(I:C) was able to prevent diabetes in NOD (non-obese diabetic) mice 38 , but it was shown in diabetes-prone bio-breeding (DP-BB) rats that poly(I:C) can accelerate 39,40 or prevent diabetes, depending on the dosage used 41 . These contradictory observations may be partially explained by differences in doses and different kinetics of poly(I:C).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Lang

Recher

Junt

et al. 2005

Nat Med

346

258

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Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8 + T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-α production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Lang

Recher

Junt

et al. 2005

Nat Med

346

258

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“…However, virally induced cytokines and chemokines can accelerate or prevent autoimmunity depending on the host strain, age, sex, immunological competence, time, location and level of expression. For example, another viral stimulus, the synthetic double-stranded RNA poly (I:C), inducer of IFNα and other cytokines, can either prevent or exacerbate the pathogenic effects of diabetogenic viruses, depending on the genetic background and the timing of administration [39,40]. In our model, IFNβ expression in NOD islets results in an early onset of autoimmune diabetes.…”

Section: Discussionmentioning

confidence: 95%

Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNβ

et al. 2006

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Aims/hypothesis The expression of IFNβ in beta cells results in accelerated type 1 diabetes. The REG family of beta cell proliferation factors have been described as autoantigens in autoimmune diabetes. The aim of this study was to determine the effect of IFNβ on Reg expression, and the implications of this in terms of autoimmunity. Methods Reg gene expression was determined in islets from non-obese diabetic (NOD) RIP-HuIFNβ mice by cDNA microarray, quantitative real-time PCR and immunohistochemistry. The effect of IFNβ on Reg1 and Reg2 expression was assessed in the NOD insulinoma cell line NIT-1. IL-6, known to induce Reg expression, was measured in the insulitis microenvironment. Morphological studies were carried out to determine islet enlargement in this model. ResultsReg2 was upregulated in islets from the NOD RIPHuIFNβ mice at the onset of the autoimmune attack. IFNβ upregulates Reg1 and Reg2 genes in NIT-1 cells. The expression of Il6 was increased in islets from transgenic mice and in NIT-1 cells exposed to HuIFNβ. Moreover, islets from transgenic mice were enlarged compared with those from wild-type mice. Conclusions/interpretation Reg overexpression correlates well with the acceleration of diabetes in this model. The upregulation of Reg suggests that islets try to improve hyperglycaemia by regenerating the cells lost in the autoimmune attack. Reg expression is regulated by several factors such as inflammation. Therefore, the overexpression of an IFNβ-induced autoantigen (REG) in the islets during inflammation might contribute to the premature onset of diabetes.

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“…1A) demonstrates that poly I:C does not reverse inhibitory effect of B:9-23 peptide on development of diabetes in NOD mice. Although the exact reason(s) for this difference are at present unclear, a recent study show that the effect of poly I:C is dose-related; high dose poly I:C accelerates but low dose prevents diabetes in BioBreeding rats [17].…”

Section: Discussionmentioning

confidence: 99%

“…The B chain peptide, B:9-23, has been suggested to be a primary autoantigenic epitope in the pathogenesis of type 1 diabetes in NOD mice [4,5]. However, of interest, immunization of NOD mice with exogenous B: [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] peptide prevents diabetes [6].…”

Section: Introductionmentioning

confidence: 99%

Combined insulin B:9-23 self-peptide and polyinosinic–polycytidylic acid accelerate insulitis but inhibit development of diabetes by increasing the proportion of CD4+Foxp3+ regulatory T cells in the islets in non-obese diabetic mice

Fukushima

Abiru

Nagayama

et al. 2008

Biochemical and Biophysical Research Communications

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Insulin peptide B:9-23 is a major autoantigen in type 1 diabetes. Combined treatment with B:9-23 peptide and polyinosinic-polycytidylic acid (poly I:C), but neither alone, induce insulitis in normal BALB/c mice. In contrast, the combined treatment accelerated insulitis, but prevented diabetes in NOD mice. Our immuno-fluorescence study with anti-CD4/antiFoxp3 revealed that the proportion of Foxp3 positive CD4 + CD25 + regulatory T cells (Tregs) was elevated in the islets of NOD mice treated with B:9-23 peptide and poly I:C, as compared to non-treated mice. Depletion of Tregs by anti-CD25 antibody hastened spontaneous development of diabetes in non-treated NOD mice, and abolished the protective effect of the combined treatment and conversely accelerated the onset of diabetes in the treated mice.These results indicate that poly I:C combined with B:9-23 peptide promotes infiltration of both pathogenic T cells and predominantly Tregs into the islets, thereby inhibiting progression from insulitis to overt diabetes in NOD mice.

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Low Dose Poly I:C Prevents Diabetes in the Diabetes Prone BB Rat

Cited by 59 publications

References 48 publications

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNβ

Combined insulin B:9-23 self-peptide and polyinosinic–polycytidylic acid accelerate insulitis but inhibit development of diabetes by increasing the proportion of CD4+Foxp3+ regulatory T cells in the islets in non-obese diabetic mice

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