Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice

Sung, Hsiang-Hsuan; Juang, Jyuhn‐Huarng; Lin, Yu‐Chun; Kuo, Chun‐Yan; Hung, Jung‐Tung; Chen, An; Chang, Der-Ming; Chang, Sun-Yran; Hsieh, Shie-Liang; Sytwu, Huey‐Kang

doi:10.1084/jem.20031939

Cited by 71 publications

(73 citation statements)

References 36 publications

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“…However, it is unclear whether constitutive production of HO-1 in a beta cell-specific manner could prevent autoimmune diabetes and prolong graft survival following syngeneic islet transplantation. To test this idea, we first established mHo-1-transgenic NOD mice under control of the insulin promoter [31]. These animals produce high levels of HO-1 in pancreatic beta cells from birth.…”

Section: Discussionmentioning

confidence: 99%

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Huang

Chu²,

Yu³

et al. 2010

Diabetologia

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Aims/hypothesis Haem oxygenase 1 (HO-1) has strong anti-apoptotic, anti-inflammatory and antioxidative effects that help protect cells against various forms of immune attack. We investigated whether transgenic expression of Ho-1 (also known as Hmox1) in pancreatic beta cells would protect NOD mice from autoimmune damage and prolong graft survival following islet transplantation. Methods To evaluate the protective effect of beta cellspecific HO-1 in autoimmune diabetes, we used an insulin promoter-driven murine Ho-1 construct (pIns-mHo-1) to generate a transgenic NOD mouse. Transgene expression, insulitis and the incidence of diabetes in mice were characterised. Lymphocyte composition, the development of T helper (Th)1, Th2 and T regulatory (Treg) cells, T cell proliferation and lymphocyte-mediated disease transfer were analysed. The potential effects of transgenic islets and islet transplantation on apoptosis, inflammation and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) were evaluated. Results Transgenic mice showed less severe insulitis and a lower incidence of diabetes than non-transgenic control littermates. Lymphocyte composition and functions were not affected. Islets from transgenic mice expressed lower levels of proinflammatory cytokines/chemokines, proapoptotic gene expression and amounts of ROS/RNS, and were more resistant to TNF-α-and IFN-γ-induced apoptosis. Islet grafts from transgenic mice also survived longer in diabetic recipients than control islets. Conclusions/interpretation Transgenic overexpression of Ho-1 in beta cells protected NOD mice from diabetes and delayed the autoimmune destruction of islet grafts, providing valuable insight into the development of better strategies for clinical islet transplantation in patients with type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Huang

Chu²,

Yu³

et al. 2010

Diabetologia

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“…Regeneration therapy represents an approach that could potentially cure type 1 diabetes when combined with cellbased gene therapeutic strategies and immune system modulation (Sytwu et al 2003, Sung et al 2004. In ex vivo regeneration therapy, the patients' own bone marrow stem cells are transiently removed and differentiated into b-cells in vitro (Lechner & Habener 2003, Moriscot et al 2005 whereas in vivo regeneration therapy uses the patients' own cells to regenerate impaired tissues (Zulewski et al 2001, Gao et al 2003.…”

Section: Introductionmentioning

confidence: 99%

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue

Shyu

Wang

Shyr

et al. 2010

Journal of Endocrinology

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Although islet transplantation holds promise for the treatment of diabetes, the scarcity of donor tissue remains a major drawback. The aim of this study is to generate insulinproducing cells from adult human pancreatic cells isolated from surgically resected pancreatic tissue. To isolate pancreatic endocrine precursor cells from 57 surgically resected pancreases, the cells were cultured and propagated in conditioned medium after which they were differentiated in Matrigel. The resultant cells were characterized using morphology, immunofluorescent studies, expression of differentiated pancreatic islet-specific genes using quantitative reverse transcription-PCR, and glucose-induced insulin secretion through analysis of C-peptide secretion. The relationships between propagation of insulin-producing cells and clinical variables of the donor were also analyzed. Finally, insulin-producing cell function was examined in streptozotocin-induced diabetic rats. Pancreatic endocrine precursor cells were successfully cultured; insulin-producing cells cultured from soft pancreas parenchyma had a significantly higher success rate. Morphological examination revealed islet-like cluster formation upon transfer to Matrigel. The presence of the neural stem cell marker nestin, duct cell marker cytokeratin 19, and endocrine cell markers C-peptide and pancreatic and duodenal homeobox 1, was also observed. In addition, glucose-stimulated C-peptide release was significantly increased in the insulinproducing cells. Furthermore, in diabetic rats, transplantation of insulin-producing cells reduced hyperglycemia. Isolated pancreatic endocrine precursor cells from surgically resected pancreatic tissue differentiated into insulin-producing cells and showed characteristics of functional endocrine cells. Thus, surgically resected pancreatic tissue may represent an alternative source of functional insulin-producing cells.

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“…Other research groups have experimented gene transfer with the aim of controlling the autoimmune reaction against islets. [21][22][23][24][25][26][27][28] Considering the limited duration of insulin independence in recipients of islet transplantation, an important area of research is to design methods to promote islet survival. The mere immobilization of islets in alginate beads has been shown to improve islet survival both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Co-encapsulation of bioengineered IGF-II-producing cells and pancreatic islets: effect on beta-cell survival

et al. 2011

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Insulin-like growth factor-II (IGF-II) has been shown to promote pancreatic b-cell survival. We evaluated the effect of co-encapsulating islets and bioengineered IGF-II-producing cells on islet cell survival. IGF-II or green fast protein (GFP) genes were transferred into TM4 cells, and purified using a neomycin resistance gene, leading to pure cell cultures (TM4-IGF-II or TM4-GFP) with a stable overexpression of the transferred gene. Islets were co-encapsulated with TM4-IGF-II or TM4-GFP, or encapsulated alone in alginate microcapsules. Rat and mouse islet cell survival was studied in vitro and in vivo, respectively. After 12 days in culture, islet viability (dual staining, acridine orange/propidium iodide) was 83% with TM4-IGF-II, compared with 51% (Po0.05) and 41% (Po0.001) with TM4-GFP and islets alone, respectively. The study of islet necrotic centers and the evaluation of islet function, using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) assay, yielded similar results. From 125 days after transplantation, more diabetic mice maintained normoglycemia when they were transplanted with islets co-encapsulated with TM4-IGF-II (4/7). A significant difference for the maintenance of normoglycemia was observed between recipients of islets co-encapsulated with TM4-IGF-II versus islets alone (P¼0.023), or with TM4-GFP (P¼0.048). In conclusion, the co-encapsulation of islets with bioengineered IGF-II-producing cells promotes islet cell survival.

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Transgenic Expression of Decoy Receptor 3 Protects Islets from Spontaneous and Chemical-induced Autoimmune Destruction in Nonobese Diabetic Mice

Cited by 71 publications

References 36 publications

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Alleviation of hyperglycemia in diabetic rats by intraportal injection of insulin-producing cells generated from surgically resected human pancreatic tissue

Co-encapsulation of bioengineered IGF-II-producing cells and pancreatic islets: effect on beta-cell survival

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