Type 1 diabetes genes and pathways shared by humans and NOD mice

Wicker, Linda S.; Clark, J. Stephen; Fraser, Heather I.; Garner, Valerie E S; González-Muñoz, Andrea; Healy, Barry; Howlett, Sarah; Hunter, Kara; Rainbow, Dan; Rosa, Raymond; Smink, Luc J.; Todd, John A.; Peterson, Laurence B.

doi:10.1016/j.jaut.2005.09.009

Cited by 134 publications

(102 citation statements)

References 57 publications

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“…A number of researchers have identified strategies for the treatment and prevention of diabetes in NOD mice [21][22][23][24][25][26][27][28][29][30][31][32][33]. For example, anti-CD3 treatment in NOD mice formed the basis for a clinical trial of anti-CD3 monoclonal antibody therapy in human T1D models.…”

Section: Introductionmentioning

confidence: 99%

Differentiation and Transplantation of Functional Pancreatic Beta Cells Generated from Induced Pluripotent Stem Cells Derived from a Type 1 Diabetes Mouse Model

Jeon

Lim

Kim

et al. 2012

Stem Cells and Development

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The nonobese diabetic (NOD) mouse is a classical animal model for autoimmune type 1 diabetes (T1D), closely mimicking features of human T1D. Thus, the NOD mouse presents an opportunity to test the effectiveness of induced pluripotent stem cells (iPSCs) as a therapeutic modality for T1D. Here, we demonstrate a proof of concept for cellular therapy using NOD mouse-derived iPSCs (NOD-iPSCs). We generated iPSCs from NOD mouse embryonic fibroblasts or NOD mouse pancreas-derived epithelial cells (NPEs), and applied directed differentiation protocols to differentiate the NOD-iPSCs toward functional pancreatic beta cells. Finally, we investigated whether the NPE-iPSC-derived insulin-producing cells could normalize hyperglycemia in transplanted diabetic mice. The NOD-iPSCs showed typical embryonic stem cell-like characteristics such as expression of markers for pluripotency, in vitro differentiation, teratoma formation, and generation of chimeric mice. We developed a method for stepwise differentiation of NOD-iPSCs into insulin-producing cells, and found that NPE-iPSCs differentiate more readily into insulin-producing cells. The differentiated NPE-iPSCs expressed diverse pancreatic beta cell markers and released insulin in response to glucose and KCl stimulation. Transplantation of the differentiated NPE-iPSCs into diabetic mice resulted in kidney engraftment. The engrafted cells responded to glucose by secreting insulin, thereby normalizing blood glucose levels. We propose that NODiPSCs will provide a useful tool for investigating genetic susceptibility to autoimmune diseases and generating a cellular interaction model of T1D, paving the way for the potential application of patient-derived iPSCs in autologous beta cell transplantation for treating diabetes.

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Section: Introductionmentioning

confidence: 99%

Differentiation and Transplantation of Functional Pancreatic Beta Cells Generated from Induced Pluripotent Stem Cells Derived from a Type 1 Diabetes Mouse Model

Jeon

Lim

Kim

et al. 2012

Stem Cells and Development

View full text Add to dashboard Cite

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“…1 Much of our understanding of T1D has come from the study of disease in the nonobese diabetic (NOD) mouse. 2,3 In addition to being a model of spontaneous T1D, NOD mice spontaneously develop other tissue-related autoimmune responses. 2,4 Several genetic loci have been associated with susceptibility and development of diabetes in both humans and NOD mice.…”

Section: Introductionmentioning

confidence: 99%

“…5 Multiple candidate genes have been identified that contribute to the genetic susceptibility of NOD mice to autoimmune diseases, including MHC class II, Il2 and Ctla4. 2,3 Natural killer (NK) cells are large granular lymphocytes that are able to lyse virally-infected and transformed cells. 6 Interestingly, several NK anomalies have been linked with diabetes.…”

Section: Introductionmentioning

confidence: 99%

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

et al. 2008

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The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.

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“…Since Treg are generated intrathymically by antigenic stimulation [39,40] and the same antigen can also cause deletion [40] of cells expressing the same receptor as Treg (a surprising notion which may depend on encounter of antigen in different thymic niches), it is not easy to decide whether certain experimental manipulations have an impact on recessive rather than dominant tolerance. Certainly, there is no formal genetic analysis that examines whether genetic factors that contribute to type 1 diabetes, such as Ptpn 22, Iddm2 or CD25 [41], do so by affecting recessive or dominant tolerance. Strong evidence for an essential role of recessive tolerance appears to be confined to a monogenic autoimmune disease caused by the disruption of the murine autoimmune regulator (AIRE) gene, where both recessive and dominant tolerances were investigated in a specific experimental setting [42], and it was concluded that intrathymic deletion, but not generation, of Treg was impaired; however, additional experiments in genetically deficient mice that would definitely exclude a role of Treg are still required to disprove dominant tolerance as the key contributor to the prevention of autoimmune disease.…”

Section: Intrathymic Deletion: Where and When?mentioning

confidence: 99%

Central tolerance: Essential for preventing autoimmune disease?

Boehmer

2009

Eur J Immunol

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Recessive central tolerance of developing T cells is caused by antigen‐induced deletion of immature cortical double positive and medullary single positive thymocytes in the absence of TCR editing. There are few examples where it can be convincingly shown that recessive tolerance plays an essential role in preventing autoimmune disease. This is in part due to the fact that genetic factors predisposing to autoimmune disease could conceivably contribute to both recessive tolerances in the thymus and antigen‐induced generation of Treg. Of considerable interest is the notion that several epitopes recognized by disease‐causing T‐cell clones exhibit poor class II MHC binding consistent with the notion that the limited availability of such epitopes in the thymus could lead to failing recessive tolerance, while more abundant quantities in peripheral lymphoid tissues could result in activation of T cells that have escaped central tolerance.

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Type 1 diabetes genes and pathways shared by humans and NOD mice

Cited by 134 publications

References 57 publications

Differentiation and Transplantation of Functional Pancreatic Beta Cells Generated from Induced Pluripotent Stem Cells Derived from a Type 1 Diabetes Mouse Model

Differentiation and Transplantation of Functional Pancreatic Beta Cells Generated from Induced Pluripotent Stem Cells Derived from a Type 1 Diabetes Mouse Model

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

Central tolerance: Essential for preventing autoimmune disease?

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