The Clinical Impact of Islet Transplantation

Fiorina, Paolo; Shapiro, A M James; Ricordi, Camillo; Secchi, Antonio

doi:10.1111/j.1600-6143.2008.02353.x

Cited by 206 publications

(153 citation statements)

References 38 publications

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“…Considering that intensive treatment with exogenous insulin only delays the occurrence of T1D complications, more strategies have been explored to improve outcomes of patients with T1D. To date, islet cell transplantation, pancreas transplantation, and anti-CD3 mAb administration have been authorized for clinical use (9,16,17). Although pancreas transplantation achieved insulin independence in 60% of subjects at 4 years after the transplant (with a median graft survival time of 9 years, according to the United Network for Organ Sharing data registry analysis), the surgical procedure is still associated with a substantial mortality rate (78% of individuals survived at 1 year) (18).…”

Section: Discussionmentioning

confidence: 99%

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

et al. 2014

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Type 1 diabetes (T1D) is one of the major autoimmune diseases affecting children and young adults worldwide. To date, the different immunotherapies tested have achieved insulin independence in <5% of treated individuals. Recently, a novel hematopoietic stem cell (HSC)-based strategy has been tested in individuals with new-onset T1D. The aim of this study was to determine the effects of autologous nonmyeloablative HSC transplantation in 65 individuals with new-onset T1D who were enrolled in two Chinese centers and one Polish center, pooled, and followed up for 48 months. A total of 59% of individuals with T1D achieved insulin independence within the first 6 months after receiving conditioning immunosuppression therapy (with antithymocyte globulin and cyclophosphamide) and a single infusion of autologous HSCs, and 32% remained insulin independent at the last time point of their follow-up. All treated subjects showed a decrease in HbA 1c levels and an increase in C-peptide levels compared with pretreatment. Despite a complete immune system recovery (i.e., leukocyte count) after treatment, 52% of treated individuals experienced adverse effects. Our study suggests the following: 1) that remission of T1D is possible by combining HSC transplantation and immunosuppression; 2) that autologous nonmyeloablative HSC transplantation represents an effective treatment for selected individuals with T1D; and 3) that safer HSC-based therapeutic options are required.The incidence of type 1 diabetes (T1D) has been significantly increasing worldwide in the last decade, thus becoming the most common autoimmune disorder in children (1). T1D is characterized by a selective and aggressive destruction of insulin-producing b-cells orchestrated by autoreactive T cells (2,3). Unfortunately, exogenous insulin therapy does not always achieve the necessary metabolic control (4), nor does it prevent the occurrence of disease-associated degenerative macrovascular and microvascular complications (5) or halt b-cell decline (6).The concept of the use of immunotherapeutic strategy to cure T1D has emerged from hallmark data generated using the NOD mouse model and has allowed for a better understanding of the pathogenesis of T1D (7). Several clinical trials-designed based on the preclinical successful targeting of components of innate and adaptive immune responses-performed thus far have failed to cure

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Section: Discussionmentioning

confidence: 99%

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

et al. 2014

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“…However, the question of whether longterm diabetes complications are halted or reversed by islet transplantation is still not fully known. Studies from other groups have shown that restoration of islet function may improve quality of life, decrease the number of hypoglycaemic episodes and be potentially protective against longterm complications in diabetic patients [24].…”

Section: Introductionmentioning

confidence: 99%

Regression of diabetic complications by islet transplantation in the rat

et al. 2009

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Aims/hypothesis Type 1 diabetes is a chronic disease leading to complications such as peripheral neuropathies, nephropathy and cardiovascular disease. Pancreatic islet transplantation is being extensively investigated for blood glucose control in animals and in human type 1 diabetic patients, but the question of whether it can reverse long-term diabetic complications has not been fully explored. We investigated the effects of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes.Methods Three groups of rats were used: healthy controls, diabetic and diabetic rats transplanted with microencapsulated islets at 2 months after diabetes induction, when neuropathy was detectable by a decrease in tail nerve conduction velocity (NCV) and impaired nociceptive thresholds. Blood glucose levels and body weight were measured weekly. The variables considered were: thermal (hot plate test) and mechanical sensitivity (Randal-Selitto paw withdrawal test), NCV and Na+, K+-ATPase activity in the sciatic nerve. At the end of the experiments hearts were removed for morphometric determination and myocyte number, and kidneys removed for histological examination. Results Islet transplantation in diabetic rats induced normoglycaemia in a few days, accompanied by a rapid rise in body weight and amelioration of impaired nociceptive thresholds, as well as normalisation of NCV and Na + , K + -ATPase, which were both about 25% below normal in diabetic rats. Myocyte loss was reduced (−34%) by islet transplantation and the observed mild kidney damage of diabetic rats was prevented. Conclusions/interpretation Besides controlling glycaemia, transplantation of microencapsulated pancreatic islets induced almost complete regression of neuropathy and prevented cardiovascular alterations.

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“…A utoimmune type 1 diabetes (T1D) results from autoimmune attack on insulin-secreting β cells and subsequent insulin deficiency (1). Cure of T1D requires both reversal of autoimmunity and resupply of insulin-secreting β cells by islet transplantation or augmentation of endogenous β-cell regeneration (2). Because of the lack of donors for islet transplantation and because islet grafts only last for ∼3 y (3), augmentation of endogenous β-cell regeneration would be the more favorable approach.…”

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confidence: 99%

Growth factors and medium hyperglycemia induce Sox9⁺ductal cell differentiation into β cells in mice with reversal of diabetes

Zhang

Lin

et al. 2016

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

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We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9 + (Sox9 + ) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9 + ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin-or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9 + ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300-450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9 + ductal cell differentiation into β cells in adult mice.

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The Clinical Impact of Islet Transplantation

Cited by 206 publications

References 38 publications

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

Regression of diabetic complications by islet transplantation in the rat

Growth factors and medium hyperglycemia induce Sox9⁺ductal cell differentiation into β cells in mice with reversal of diabetes

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The Clinical Impact of Islet Transplantation

Cited by 206 publications

References 38 publications

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in New-Onset Type 1 Diabetes: A Multicenter Analysis

Regression of diabetic complications by islet transplantation in the rat

Growth factors and medium hyperglycemia induce Sox9+ductal cell differentiation into β cells in mice with reversal of diabetes

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Growth factors and medium hyperglycemia induce Sox9⁺ductal cell differentiation into β cells in mice with reversal of diabetes