Reversal of Diabetes in Pancreatectomized Pigs After Transplantation of Neonatal Porcine Islets

Kin, Tatsuya; Korbutt, Gregory S.; Kobayashi, T; Dufour, Jannette M.; Rajotte, Ray V.

doi:10.2337/diabetes.54.4.1032

Cited by 62 publications

(49 citation statements)

References 53 publications

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“…We feel, however, that the high levels of sirolimus to which the animals are exposed may accurately represent the high peak drug concentrations within the portal circulation, to which human and large animal islet grafts are exposed after being infused into the recipient liver [37]. Similar decreases in insulin response to glucose have been reported in an allograft porcine model of islet transplantation and in the clinical setting of patients who receive islet transplantation [27,38]. In both reports transplant recipients received sirolimus as part of their immunosuppressive regime and demonstrated elevated glucose following a glucose challenge test.…”

Section: Discussionmentioning

confidence: 97%

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The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

et al. 2006

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Aims/hypothesis The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue. Methods HDCs (n=4), NPIs (n=9) and human islets (n=5) were cultured with and without sirolimus (20 ng/ml) for 6 days. Results HDCs and NPIs cultured with sirolimus showed a 50 and 28% decrease, respectively, in cell number relative to control (p<0.05). Control cultures expanded 1.65-and 2.44-fold relative to time 0. Decreases in cell number of sirolimus-treated HDCs were not due to apoptosis as measured by TUNEL staining. No functional effects on human islets or NPIs were observed following static incubation with high glucose. Treatment of syngeneically transplanted and naïve BALC/c mice with sirolimus resulted in altered OGTT profiles with prolonged elevation of hyperglycaemia and weight gain. There was no difference in graft and organ insulin content between treatment groups. Conclusions/interpretation Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance.

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Section: Discussionmentioning

confidence: 97%

“…NPIs constitute a potential source of cells for clinical transplantation because of their inherent ability for proliferation and differentiation [26]. Recently, we provided the first evidence that allogeneic NPIs can reverse diabetes in a large animal model [27,28].…”

mentioning

confidence: 99%

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

et al. 2006

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“…189,190 Some groups have attempted to incorporate biological cues such as MMPs and vascular endothelial growth factor to facilitate ECM degradation, cell proliferation, angiogenesis, or regeneration. [191][192][193] Amino acid sequence-Arg-Gly-Asp-(RGD)…”

Section: Mechanical Propertymentioning

confidence: 99%

Three-Dimensional Scaffolds for Tissue Engineering Applications: Role of Porosity and Pore Size

Loh

Choong

2013

Tissue Engineering Part B: Reviews

2,070

1,446

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Tissue engineering applications commonly encompass the use of three-dimensional (3D) scaffolds to provide a suitable microenvironment for the incorporation of cells or growth factors to regenerate damaged tissues or organs. These scaffolds serve to mimic the actual in vivo microenvironment where cells interact and behave according to the mechanical cues obtained from the surrounding 3D environment. Hence, the material properties of the scaffolds are vital in determining cellular response and fate. These 3D scaffolds are generally highly porous with interconnected pore networks to facilitate nutrient and oxygen diffusion and waste removal. This review focuses on the various fabrication techniques (e.g., conventional and rapid prototyping methods) that have been employed to fabricate 3D scaffolds of different pore sizes and porosity. The different pore size and porosity measurement methods will also be discussed. Scaffolds with graded porosity have also been studied for their ability to better represent the actual in vivo situation where cells are exposed to layers of different tissues with varying properties. In addition, the ability of pore size and porosity of scaffolds to direct cellular responses and alter the mechanical properties of scaffolds will be reviewed, followed by a look at nature's own scaffold, the extracellular matrix. Overall, the limitations of current scaffold fabrication approaches for tissue engineering applications and some novel and promising alternatives will be highlighted.

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“…In addition, the inhibition of anti-rat antibody production in recipient mice able alternative source of insulin-producing tissue for clinical transplantation (10,12), and currently represents treated with anti-LFA-1 mAb suggests that anti-LFA-1 mAb therapy successfully interrupts the indirect pathone the most promising sources of islets to meet the high demand for human islet transplantation. Many experiway of antigen presentation.…”

Section: Discussionmentioning

confidence: 99%

Monotherapy with Anti-LFA-1 Monoclonal Antibody Promotes Long-Term Survival of Rat Islet Xenografts

et al. 2008

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Previously we demonstrated that anti-LFA-1 monoclonal (mAb) could promote long-term survival of discordant porcine islet xenografts in mice. The aim of this study, therefore, was to determine whether a shortterm administration of anti-LFA-1 mAb would promote long-term survival of concordant rat islet xenografts in mice, and whether combining short-term administration of anti-LFA-1 mAb therapy with an immunosuppressive drug, rapamycin, would facilitate islet xenograft survival. Streptozotocin-induced diabetic BALB/c mice were transplanted with 500 Wistar-Furth rat islets under the kidney capsule and were either left untreated or treated with short-term administration of rapamycin (0.2 mg/kg) alone, anti-LFA-1 mAb (0.2 mg/ dose) alone, or a combination of rapamycin and anti-LFA-1 mAb using the same doses. All untreated mice rejected their grafts by 24 days posttransplantation with a mean graft survival time of 18.8 ± 2.5 days posttransplantation (n = 5). All mice treated with rapamycin alone had prolonged islet graft survival but eventually rejected their islet grafts by 81 days posttransplantation. In contrast, the majority of the mice (27/ 28) treated with anti-LFA-1 mAb alone maintained long-term normoglycemia (>100 days). Rapamycin in combination with anti-LFA-1 mAb proved equally effective with 29 of 30 mice maintaining normoglycemia for more than 100 days posttransplantation. Low levels of mouse anti-rat antibodies, as well as a decrease in the degree of mononuclear cell infiltration of the islet graft, closely correlated with long-term islet xenograft survival. These results demonstrate that monotherapy with anti-LFA-1 mAb is highly effective in promoting long-term survival of rat islet xenografts and that combination of anti-LFA-1 mAb with rapamycin does not facilitate nor abrogate the induction of long-term xenograft survival by anti-LFA-1 mAb therapy in BALB/c mice. Our study indicates that immunomodulation through mAb therapy could form a significant component of future antirejection therapies in clinical islet xenotransplantation.

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Reversal of Diabetes in Pancreatectomized Pigs After Transplantation of Neonatal Porcine Islets

Cited by 62 publications

References 53 publications

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

Three-Dimensional Scaffolds for Tissue Engineering Applications: Role of Porosity and Pore Size

Monotherapy with Anti-LFA-1 Monoclonal Antibody Promotes Long-Term Survival of Rat Islet Xenografts

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