Loss of pancreatic islet tolerance induced by β-cell expression of interferon-γ

Sarvetnick, Nora; Shizuru, Judith A.; Liggitt, Denny; Martin, Luis; McIntyre, Bradley W.; Gregory, Alexander Michelotti; Parslow, Tristram G.; Stewart, Timothy A.

doi:10.1038/346844a0

Cited by 325 publications

(151 citation statements)

References 18 publications

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“…[1][2][3][4] In addition, the proliferation and differentiation of pancreatic duct cells play critical roles in the transgenic mouse model of islet regeneration that we developed and characterized. 36 Indeed, the observation that endocrine cell differentiation frequently accompanies pancreatic duct cell carcinomas suggests that duct cell proliferation can lead to islet neogenesis, 37,38 even though no clinical symptoms were evident in our KGF transgenic mice described here.…”

Section: Discussionmentioning

confidence: 72%

Pancreatic Expression of Keratinocyte Growth Factor Leads to Differentiation of Islet Hepatocytes and Proliferation of Duct Cells

Krakowski

Kritzik

Jones

et al. 1999

The American Journal of Pathology

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127

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Keratinocyte growth factor , (KGF) , a member of the fibroblast growth factor (FGF) family , is involved in wound healing. It also promotes the differentiation of many epithelial tissues and proliferation of epithelial cells as well as pancreatic duct cells. Additionally, many members of the highly homologous FGF family (including KGF) , influence both growth and cellular morphology in the developing embryo. We have previously observed elevated levels of KGF in our interferon-␥ transgenic mouse model of pancreatic regeneration. To understand the role of KGF in pancreatic differentiation , we generated insulin promoter-regulated KGF transgenic mice. Remarkably , we have found that ectopic KGF expression resulted in the emergence of hepatocytes within the islets of Langerhans in the pancreas. Additionally , significant intraislet duct cell proliferation in the pancreata of transgenic KGF mice was observed. The unexpected appearance of hepatocytes and proliferation of intraislet duct cells in the pancreata of these mice evidently stemmed directly from local exposure to KGF. (Am J Pathol 1999, 154:683-691)

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Section: Discussionmentioning

confidence: 72%

Pancreatic Expression of Keratinocyte Growth Factor Leads to Differentiation of Islet Hepatocytes and Proliferation of Duct Cells

Krakowski

Kritzik

Jones

et al. 1999

The American Journal of Pathology

Self Cite

127

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“…Additionally, there is substantial evidence from clinical and experimental data that Th1/Th2 balance is important to the development of atopic and autoimmune diseases [2,26,27,28,29,30]. On the other hand, both Type 1 diabetes and atopic diseases have been rising during the last decades [31,32,33,34], according to the 'hygiene hypothesis' possibly due to a decrease of infectious diseases in industrialized countries [35,36].…”

Section: Discussionmentioning

confidence: 99%

Atopic eczema in early childhood could be protective against Type 1 diabetes

2003

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Aims/hypothesis. According to the Th1/Th2 paradigm Type 1 diabetes and atopic diseases are assumed to be mutually exclusive on the individual level. We analysed the association between Type 1 diabetes and atopic diseases in a case-control design in order to test the hypothesis that atopic diseases in early childhood could protect against Type 1 diabetes. Methods. We carried out a nationwide populationbased case-control study enrolling 760 cases newlydiagnosed with Type 1 diabetes under five years of age between July 1992 and December 1995 and 1871 controls randomly selected from the general population and individually matched on sex, age and place of residence. Information on atopic diseases was obtained by a mailed parent-administered questionnaire. Data were analysed by multivariate logistic regression adjusting for potential confounders (family history of diabetes, social status, duration of overall breast feeding, number of children in family, maternal age at delivery). Results. Atopic eczema was less frequent in diabetic (13.3%) than in non-diabetic children (18.0%) and was significantly associated with a reduced risk of Type 1 diabetes. The adjusted odds ratio was 0.71 (95% CI 0.53-0.96). Hay fever and asthma were not significantly associated with diabetes risk (OR 0.98 (95% CI 0.47-2.01) and 1.46 (95% CI 0.70-3.06), respectively). Conclusion/interpretation.In this large populationbased case-control study in pre-school children an inverse association was observed between atopic eczema and Type 1 diabetes. Thus, in accordance with the Th1/Th2 paradigm development of atopic eczema in early childhood could be protective against childhood Type 1 diabetes. [Diabetologia (2003) 46:784-788]

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“…In those studies there was evidence of an increased mitotic activity in ductal cells after daily administration of KGF [5], and a higher percentage of dividing ductal cells in the pancreas of transgenic mice overexpressing KGF [18]. The proliferation and differentiation of pancreatic ductal cells play important roles in experimental models of islet regeneration in rodents [22,23,24]. Thus, proliferation of pancreatic duct cells leads to an increase in the number of endocrine precursor cells which could ultimately differentiate into beta cells.…”

Section: Effect Of Kgf On Beta Cell and Ductal Cell Proliferationmentioning

confidence: 99%

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

et al. 2003

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Aims and hypothesis. Keratinocyte growth factor (KGF) is a member of the heparin-binding fibroblast growth factor family with a high degree of specificity for epithelial cells in vitro and in vivo. Our aim was to study the effect of KGF on beta-cell growth and differentiation on islet-like cell clusters derived from human fetal pancreas. Methods. We investigated the effects of KGF, in vitro, on beta-cell differentiation from undifferentiated pancreatic precursor cells and in vivo after transplantating human fetal pancreatic cells into athymic rats treated with KGF. Results. Treatment of islet-like cell clusters with KGF in vitro did not change the number of insulin producing cells, as measured by the measurement of insulin content or DNA. The in vivo treatment of recipient rats with KGF increased the number of beta cells within the grafts 8 weeks after transplantation. At this time, glucose-stimulated insulin secretion was evaluated by glucose stimulation tests in rats bearing the transplants. Measurements of human C-peptide concentrations after glucose challenge showed that the newly differentiated beta cells in the KGF-treated group were functionally competent as opposed to the control group, where the graft failed to release insulin appropriately. Conclusion/interpretation. These findings suggest that in vivo, KGF is capable of inducing human fetal beta-cell expansion. The growth promoting effect of KGF on beta cells occurred mainly through the activation of ductal cell proliferation and their subsequent differentiation into beta cells. [Diabetologia (2003) 46:822-829]

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Loss of pancreatic islet tolerance induced by β-cell expression of interferon-γ

Cited by 325 publications

References 18 publications

Pancreatic Expression of Keratinocyte Growth Factor Leads to Differentiation of Islet Hepatocytes and Proliferation of Duct Cells

Pancreatic Expression of Keratinocyte Growth Factor Leads to Differentiation of Islet Hepatocytes and Proliferation of Duct Cells

Atopic eczema in early childhood could be protective against Type 1 diabetes

Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

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