Reversal of established autoimmune diabetes by restoration of endogenous β cell function

Ryu, Shinichiro; Kodama, Shohta; Ryu, Kazuko; Schoenfeld, Daniel; Faustman, Denise L.

doi:10.1172/jci200112335

Cited by 51 publications

(66 citation statements)

References 36 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

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“…The ability to predict and prevent recurrent autoimmunity is also relevant if autologous stem cells [17] or regenerated endogenous beta cells [18,19] are used. However, despite the importance of the IGRP-specific CD8 + T cell subset for islet pathogenicity, prediction of recurrent autoimmune islet graft failure was not possible based on detection of IGRP-reactive CD8 + T cells in the peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

“…In the NOD mouse, three CTL specificities with in vivo pathogenicity have been identified. These CTL recognise peptide sequences from the insulin B chain [15][16][17][18][19][20][21][22][23] (G9C8 clone) [2], islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP 206-214 ; 8.3 clone) [3] and dystrophia myotonica kinase (AI4 clone) [4]. Together, these CTL populations constitute a large proportion (up to 60%) of the CD8 + T cells within the pancreatic islets of prediabetic NOD mice [4,5].…”

Section: Introductionmentioning

confidence: 99%

Prospective prediction of spontaneous but not recurrent autoimmune diabetes in the non-obese diabetic mouse

et al. 2007

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Aims/hypothesis Type 1 diabetes is a T cell-mediated autoimmune disease with a clinically silent prodrome, during which prediction and treatment of disease are theoretically possible. Using retrospective analysis, spontaneous disease in the non-obese diabetic (NOD) mouse has been correlated with islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-reactive CD8 + T cells in the peripheral blood. In this study, we determined prospectively whether IGRP-reactive T cells in peripheral blood could predict disease occurrence. Since recurrent autoimmunity is an important contributor to transplant failure, we also determined whether failure of islet grafts (syngeneic and allogeneic) could be predicted by the presence of circulating autoreactive T cells. Materials and methods Peripheral blood samples were taken weekly from female NOD mice between the ages of 8 and 30 weeks and from NOD mice transplanted with NODscid islets. Peripheral blood cells and islet grafts were analysed for the presence of IGRP-reactive CD8 + T cells by flow cytometry. Results Prospective analysis of peripheral blood IGRPreactive T cells in the prediabetic period predicted disease development with a sensitivity of 100% and a specificity of 60%, resulting in positive and negative predictive values of 85 and 100%, respectively. Significant proportions of IGRP-reactive T cells were found in the grafts, but not in peripheral blood of NOD mice undergoing syngeneic and allogeneic rejection. Conclusions/interpretation The occurrence of spontaneous diabetes can be predicted prospectively by measuring peripheral blood autoreactive T cells. Rejection of syngeneic or allogeneic islets is associated with large populations of autoreactive CD8 + T cells within islets, suggesting that immunodominant autoreactive T cells during the prediabetic period are also responsible for autoimmune graft rejection.

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“…My laboratory launched an immune intervention trial in diabetic patients with long-standing disease (a mean of 15 years) who had 'no' fasting or stimulated C-peptide as assessed by conventional clinically approved assays [12]. We were motivated to apply an immune intervention in long-term diabetic patients because the immunotherapy (Bacillus Calmette-Guerin, BCG) had been successful in end stages, not just new-onset disease, in an animal model of type 1 diabetes, the NOD mouse [13]. A condition of enrolment in our human clinical trial was no fasting or stimulated C-peptide by traditional assay methods that detect C-peptide to a lower level of about 40 pmol/l.…”

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confidence: 99%

Why were we wrong for so long? The pancreas of type 1 diabetic patients commonly functions for decades

Faustman

2013

Diabetologia

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Reversal of established autoimmune diabetes by restoration of endogenous β cell function

Cited by 51 publications

References 36 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

Prospective prediction of spontaneous but not recurrent autoimmune diabetes in the non-obese diabetic mouse

Why were we wrong for so long? The pancreas of type 1 diabetic patients commonly functions for decades

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