Adenoviral overproduction of interleukin-1 receptor antagonist increases beta cell replication and mass in syngeneically transplanted islets, and improves metabolic outcome

Téllez, Noèlia; Montolio, Marta; Altimiras, Elisabet Estil·les; Escoriza, Jessica; Soler, Joan; Montanya, Eduard

doi:10.1007/s00125-006-0548-1

Cited by 31 publications

(20 citation statements)

References 56 publications

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“…IL-1␤ has been shown to break tolerance (30) and facilitate islet antigen presentation (6). In other studies, IL-1Ra inhibited mouse islet allograft rejection (15), increased islet beta cell function during transplantation (31), and improved disease parameters in patients with type 2 diabetes (32). AAT was shown to induce IL-1Ra in human PBMCs (33).…”

Section: Discussionmentioning

confidence: 97%

α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

Lewis

Mizrahi²,

Toledano³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

175

220

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Human pancreatic islet transplantation offers diabetic patients tight glucose control but has low graft survival rates. The immunosuppressive drugs that are administered to graft recipients lack the antiinflammatory benefits of corticosteroids because of their diabetogenic effects. The serum protease inhibitor ␣1-antitrypsin (AAT) possesses antiinflammatory properties and reduces cytokine-mediated islet damage. In the present study, diabetic mice were grafted with allogeneic islets and treated with AAT monotherapy (n ‫؍‬ 24). After 14 days of treatment, mice remained normoglycemic and islet allografts were functional for up to 120 treatment-free days. After graft removal and retransplantation, mice accepted same-strain islets but rejected third-strain islets, thus confirming that specific immune tolerance had been induced.

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Section: Discussionmentioning

confidence: 97%

α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

Lewis

Mizrahi²,

Toledano³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

175

220

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“…That hyperglycaemia itself can decrease insulin secretion has led to the concept of glucose toxicity, which implies the development of irreversible damage to cellular components of the insulin production pathway over time [24,25]. The effects of the pro-inflammatory cytokine IL-1␤ have been conclusively shown to impair glucose-stimulated insulin production in mouse, rat and human islets, and to increase ␤-cell death [19,20,26]. In this study, we found that MafA-overexpressing PDMSCs are more resistant to hyperglycaemia-induced or hyperglycaemia and oxidative stress-induced toxicity and damage compared to PDMSCs with the vector control ( Fig.…”

Section: Discussionmentioning

confidence: 99%

MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin+ cells

Chiou

Chen

Chang

et al. 2010

Journal of Cellular and Molecular Medicine

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MafA is a pancreatic transcriptional factor that controls β-cell-specific transcription of the insulin gene. However, the role of MafA in the regulation of pancreatic transdifferentiation and reprogramming in human stem cells is still unclear. In this study, we investigate the role of MafA in placenta-derived multipotent stem cells (PDMSCs) that constitutively expressed Oct-4 and Nanog. PDMSCs were isolated and transfected with MafA using a lentivector. Our results showed that overexpression of MafA in PDMSCs significantly up-regulated the expression of pancreatic development-related genes (Sox17, Foxa2, Pdx1 and Ngn3). Microarray analysis suggested that the gene expression profile of MafA-overexpressing PDMSCs was similar to that of pancreas and islet tissues. MafA increased the expression levels of the mRNAs of NKx2.2, Glut2, insulin, glucagons and somatostatin, and further facilitated the differentiation of PDMSCs into insulin+ cells. The glucose-stimulated responses to insulin and c-peptide production in MafA-overexpressing PDMSCs were significantly higher than in PDMSCs with vector control. Our results indicated that MafA-overexpressing PDMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than PDMSCs carrying the vector control were. Importantly, the expression of MafA in PDMSCs xenotransplanted into immunocompromised mice improved the restoration of blood insulin levels to control values and greatly prolonged the survival of graft cells in immunocompromised mice with STZ-induced diabetes. In summary, these data suggest that MafA plays a novel role in the reprogramming of stem cells into pancreatic β-progenitors, promotes the islet-like characteristics of PDMSCs, as well as functionally enhances insulin production to restore the regulation of blood glucose levels in transplanted grafts.

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“…This selectivity is further supported by studies showing that maturation of the β cell makes it prone to the toxic effects of IL-1β (118). On the basis of animal studies, IL-1β plays an important role in destruction of transplanted islet grafts (119)(120)(121)(122)(123), and blocking cytokines in clinical islet transplantation has also been suggested as a future intervention to prevent graft destruction (124).…”

Section: β-Cell Destruction and Hdacimentioning

confidence: 92%

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

Christensen

Dahllöf

Lundh

et al. 2011

Mol Med

232

167

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Both common forms of diabetes have an inflammatory pathogenesis in which immune and metabolic factors converge on interleukin-1β as a key mediator of insulin resistance and β-cell failure. In addition to improving insulin resistance and preventing β-cell inflammatory damage, there is evidence of genetic association between diabetes and histone deacetylases (HDACs); and HDAC inhibitors (HDACi) promote β-cell development, proliferation, differentiation and function and positively affect late diabetic microvascular complications. Here we review this evidence and propose that there is a strong rationale for preclinical studies and clinical trials with the aim of testing the utility of HDACi as a novel therapy for diabetes.

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Adenoviral overproduction of interleukin-1 receptor antagonist increases beta cell replication and mass in syngeneically transplanted islets, and improves metabolic outcome

Abstract: Aims/hypothesis Interleukin-1 receptor antagonist (IL1RN, also known as IL1RA) is a naturally occurring inhibitor of IL-1 action and its overproduction protects pancreatic islets from the deleterious effects of IL-1β on beta cell replication, apoptosis and function.

Cited by 31 publications

References 56 publications

α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

α1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice

MafA promotes the reprogramming of placenta-derived multipotent stem cells into pancreatic islets-like and insulin+ cells

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

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