International islet transplant registry report

Bretzel, Reinhard G.; Hering, Bernhard J.; Schultz, Andreas; Geier, Christoph; Federlin, K.

doi:10.1007/978-94-009-0165-0_15

Cited by 96 publications

(103 citation statements)

References 9 publications

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“…For many years, the clinical outcome of allogeneic islet transplantations was very poor, with less than 10% of the recipients being insulin-independent after 1 year [1]. However, the recently introduced Edmonton Protocol, which applies a steroid-and cyclosporine-free immunosuppressive regime, has improved insulin independence 1 year posttransplantation to approximately 80% [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

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Better vascular engraftment and function in pancreatic islets transplanted without prior culture

Olsson

Carlsson

2005

Diabetologia

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Aims/hypothesis: Recent studies suggest that donor endothelial cells may contribute to islet graft revascularisation. Since islet endothelial cells disappear during culture, we hypothesised that transplantation of islets without prior culture is beneficial for their engraftment. Methods: Cultured (4-7 days) or freshly isolated islets (<4 h after donor pancreas extirpation) were syngeneically transplanted into Wistar-Furth rats and C57Bl/6 mice beneath the renal capsule. Islet graft revascularisation was evaluated by measuring vascular density, blood flow and tissue oxygen tension. Islet graft function was investigated by a minimal islet mass model in inbred mice (C57Bl/6). Results: Four days after implantation, the partial pressure of oxygen (pO 2 ) in the transplanted cultured islets was less than 10 mmHg (1.33 kPa), but tended to be higher in grafts composed of freshly isolated islets. The pO 2 in the grafts of freshly isolated islets had more than doubled 4 weeks later, whereas the pO 2 in the grafts of cultured islets remained at values similar to those recorded 4 days after transplantation. Transplanted freshly isolated islets also had a higher vascular density than transplanted cultured islets (∼40 vs ∼25% of that in endogenous islets) when investigated 1 month post-implantation. When applying a minimal islet mass model in inbred mice, 200 freshly isolated islets cured alloxan-diabetic mice in all cases, whereas only 33% of the group receiving similar numbers of cultured islets were cured. Conclusions/interpretation: Transplantation of pancreatic islets without prior culture is beneficial for their vascular engraftment and function.

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Section: Introductionmentioning

confidence: 99%

“…However, the recently introduced Edmonton Protocol, which applies a steroid-and cyclosporine-free immunosuppressive regime, has improved insulin independence 1 year posttransplantation to approximately 80% [1][2][3]. The Edmonton Protocol used freshly isolated islets for transplantation [2].…”

Section: Introductionmentioning

confidence: 99%

Better vascular engraftment and function in pancreatic islets transplanted without prior culture

Olsson

Carlsson

2005

Diabetologia

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“…Allografted adult human islets are capable of reversing diabetes with results improving in some 2 but not all centers. 3 Fetal pancreatic tissue is an alternative, the potential of which has not been fully realized. 4 An alternative approach to the treatment of type I diabetes is the use of liver cells that have been genetically altered to produce insulin.…”

Section: Introductionmentioning

confidence: 99%

Function of a genetically modified human liver cell line that stores, processes and secretes insulin

Tuch

Szymańska

et al. 2003

Gene Ther

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An alternative approach to the treatment of type I diabetes is the use of genetically altered neoplastic liver cells to synthesize, store and secrete insulin. To try and achieve this goal we modified a human liver cell line, HUH7, by transfecting it with human insulin cDNA under the control of the cytomegalovirus promoter. The HUH7-ins cells created were able to synthesize insulin in a similar manner to that which occurs in pancreatic b cells. They secreted insulin in a regulated manner in response to glucose, calcium and theophylline, the dose-response curve for glucose being near-physiological. Perifusion studies showed that secretion was rapid and tightly controlled. Removal of calcium resulted in loss of glucose stimulation while addition of brefeldin A resulted in a 30% diminution of effect, indicating that constitutive release of insulin occurred to a small extent. Insulin was stored in granules within the cytoplasm. When transplanted into diabetic immunoincompetent mice, the cells synthesized, processed, stored and secreted diarginyl insulin in a rapid regulated manner in response to glucose.Constitutive release of insulin also occurred and was greater than regulated secretion. Blood glucose levels of the mice were normalized but ultimately became subnormal due to continued proliferation of cells. Examination of the HUH7-ins cells as well as the parent cell line for b cell transcription factors showed the presence of NeuroD but not PDX-1. PC1 and PC2 were also present in both cell types. Thus, the parent HUH7 cell line possessed a number of endocrine pancreatic features that reflect the common endodermal ancestry of liver and pancreas, perhaps as a result of ontogenetic regression of the neoplastic liver cell from which the line was derived. Introduction of the insulin gene under the control of the CMV promoter induced changes in these cells to make them function to some extent like pancreatic b cells. Our results support the view that neoplastic liver cells can be induced to become substitute pancreatic b cells and become a therapy for the treatment of type I diabetes.

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“…Insulin replacement by injection, the current treatment, fails to replicate the precise control of fuel homeostasis afforded by normal regulation of insulin secretion in response to glucose and other physiological cues. Islet transplantation has therefore been investigated as an alternative to insulin injection therapy for more than 3 decades (6,7). Success in this area had been very limited until a recent trial in Edmonton, Alberta, Canada, in which a combination of mild immunosuppressive agents were used in conjunction with freshly isolated islet tissue to achieve insulin independence in seven successive patients studied for up to 14.9 months post-transplant (8).…”

mentioning

confidence: 99%

Expression of the Transcription Factor STAT-1α in Insulinoma Cells Protects against Cytotoxic Effects of Multiple Cytokines

Chen¹,

Hohmeier²,

Newgard³

2001

Journal of Biological Chemistry

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Destruction of pancreatic islet ␤-cells in type 1 diabetes appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as interferon (IFN)-␥, interleukin (IL)-Type 1 diabetes is caused by autoimmune destruction of pancreatic islet ␤-cells. Destruction of ␤-cells appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as IFN-␥, 1 IL-1␤, and TNF-␣ that such cells produce (1-5). Insulin replacement by injection, the current treatment, fails to replicate the precise control of fuel homeostasis afforded by normal regulation of insulin secretion in response to glucose and other physiological cues. Islet transplantation has therefore been investigated as an alternative to insulin injection therapy for more than 3 decades (6, 7). Success in this area had been very limited until a recent trial in Edmonton, Alberta, Canada, in which a combination of mild immunosuppressive agents were used in conjunction with freshly isolated islet tissue to achieve insulin independence in seven successive patients studied for up to 14.9 months post-transplant (8).Unfortunately, enthusiasm for this important finding is tempered by the fact that the number of human pancreata available for islet transplantation in the United States is on the order of several thousand per year (6, 7), which does not approach the number of patients that could benefit from this new form of therapy. To deal with this problem, we and others have been attempting to develop a replenishable source of cells that could serve as islet surrogates for cell-based insulin replacement in diabetes (9 -13). One working concept is that immortalized cell lines engineered for robust glucose-stimulated insulin secretion can be transplanted in the context of a cellimpermeant macroencapsulation device, preventing contact of cellular elements of the immune system with the transplanted cells (11). However, because such devices are envisioned to allow rapid exit of insulin, as well as highly efficient equilibration of nutrients, oxygen, and waste products, it is anticipated that soluble mediators of immunological damage such as cytokines or reactive oxygen species will readily gain access to the cells within the device. Thus, development of methods to protect transplanted cells against diffusable, noncellular mediators of immunological destruction may be important for the eventual success of cell-based insulin replacement strategies.Recently, we described a method for selection of cell lines with resistance to the cytotoxic effects of exposure to a mixture of IL-1␤ and IFN-␥, known mediators of ␤-cell destruction in type 1 diabetes (14). This involved growth of INS-1 insulinoma cells in progressively elevated concentrations of the two cytokines over an 8-week period and selection of surviving cells. The resultant cell line, termed INS-1 res , was 80% viable after 5 days of exposure to the combination of 10 ng/ml IL-1␤ and 100 units/ml IFN-␥, while less th...

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International islet transplant registry report

Cited by 96 publications

References 9 publications

Better vascular engraftment and function in pancreatic islets transplanted without prior culture

Better vascular engraftment and function in pancreatic islets transplanted without prior culture

Function of a genetically modified human liver cell line that stores, processes and secretes insulin

Expression of the Transcription Factor STAT-1α in Insulinoma Cells Protects against Cytotoxic Effects of Multiple Cytokines

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