INDUCTION, MAINTENANCE, AND REVERSAL OF STREPTOZOTOCIN-INDUCED INSULIN-DEPENDENT DIABETES MELLITUS IN THE JUVENILE CYNOMOLGUS MONKEY (Macaca fascilularis)1

Theriault, Betty; Thistlethwaite, J. Richard; Levisetti, Matteo; Wardrip, Craig L.; Szot, Gregory L.; Bruce, David S.; Rilo, Horacio; Li, Xiantang; Gray, Gary S.; Bluestone, Jeffrey A.; Padrid, Philip

doi:10.1097/00007890-199908150-00003

Cited by 52 publications

(55 citation statements)

References 14 publications

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“…We observed no reversal of type 1 diabetes in these nontransplanted controls. Thus, single highdose STZ treatment was effective in unvaryingly establishing type 1 diabetes in our juvenile rhesus macaques, confirming earlier experience by others with high-dose (Ͼ140 mg/kg) STZ-induced type 1 diabetes in monkeys (17,18). Recovery of isolated allogeneic nonhuman primate islets.…”

Section: Resultssupporting

confidence: 88%

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Successful Reversal of Streptozotocin-Induced Diabetes With Stable Allogeneic Islet Function in a Preclinical Model of Type 1 Diabetes

et al. 2001

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The recent focus on islet transplantation as primary therapy for type 1 diabetes has heightened interest in the reversal of type 1 diabetes in preclinical models using minimal immunosuppression. Here, we demonstrated in a preclinical rhesus model a consistent reversal of all measured glycemic patterns of streptozotocin-induced type 1 diabetes. The model used single-donor islet transplantation with induction of operational tolerance. The term "operational tolerance" is used to indicate durable survival of single-donor major histocompatibility complex (MHC)-mismatched islet allografts without maintenance immunosuppressive therapy and without rejection or loss of functional islet mass or insulin secretory reserve. In this operational tolerance model, all immunosuppression was discontinued after day 14 posttransplant, and recipients recovered with excellent health. The operational tolerance induction protocol combined peritransplant anti-CD3 immunotoxin to deplete T-cells and 15-deoxyspergualin to arrest proinflammatory cytokine production and maturation of dendritic cells. T-cell deficiency was specific but temporary, in that T-celldependent responses in long-term survivors recovered to normal, and there was no evidence of increased susceptibility to infection. Anti-donor mixed lymphocyte reaction responses were positive in the long-term survivors, but all showed clear evidence of systemic T-helper 2 deviation, suggesting that an immunoregulatory rather than a deletional process underlies this operational tolerance model. This study provides the first evidence that operational tolerance can protect MHC nonhuman primate islets from rejection as well as loss of functional islet mass. Such an approach has potential to optimize individual recipient recovery from diabetes as well as permitting more widespread islet transplantation with the limited supply of donor islets.

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Section: Resultssupporting

confidence: 88%

“…The STZ (Sigma, St. Louis, MO) was mixed with 5 ml citrate buffer and infused over 1 min. As previously reported, a single large (Ͼ140 mg/kg) dose, but not smaller single or multiple STZ doses, reliably induces a type 1 diabetic state that is both similar to human type 1 diabetes and associated with similar secondary complications (17,18).…”

Section: Methodssupporting

confidence: 64%

Successful Reversal of Streptozotocin-Induced Diabetes With Stable Allogeneic Islet Function in a Preclinical Model of Type 1 Diabetes

et al. 2001

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“…The ratio of both concentrations yielded the final percent HbA1c result (HbA1c %). (31). High fasting blood glucose levels were observed in all monkeys within 24 h following STZ injection.…”

Section: Surgerymentioning

confidence: 86%

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

Hecht

Eventov‐Friedman

Rosen

et al. 2009

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

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Xenotransplantation of pig tissues has great potential to overcome the shortage of organ donors. One approach to address the vigorous immune rejection associated with xenotransplants is the use of embryonic precursor tissue, which induces and utilizes host vasculature upon its growth and development. Recently, we showed in mice that embryonic pig pancreatic tissue from embryonic day 42 (E42) exhibits optimal properties as a ␤ cell replacement therapy. We now demonstrate the proof of concept in 2 diabetic Cynomolgus monkeys, followed for 393 and 280 days, respectively. A marked reduction of exogenous insulin requirement was noted by the fourth month after transplantation, reaching complete independence from exogenous insulin during the fifth month after transplantation, with full physiological control of blood glucose levels. The porcine origin of insulin was documented by a radioimmunoassay specific for porcine C-peptide. Furthermore, the growing tissue was found to be predominantly vascularized with host blood vessels, thereby evading hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies. Durable graft protection was achieved, and most of the late complications could be attributed to the immunosuppressive protocol. While fine tuning of immune suppression, tissue dose, and implantation techniques are still required, our results demonstrate that porcine E-42 embryonic pancreatic tissue can normalize blood glucose levels in primates. Its long-term proliferative capacity, its revascularization by host endothelium, and its reduced immunogenicity, strongly suggest that this approach could offer an attractive replacement therapy for diabetes.immune-suppression ͉ rejection ͉ xeno-transplantation

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“…These Old World monkeys represent a good model for islet transplantation studies [3,7,36]. They can be rendered diabetic by the administration of streptozotocin [7,16,38,39] or by total pancreatectomy [2,40], and prior to islet transplantation the induced diabetes can be controlled by insulin injections for long periods of time.…”

Section: Discussionmentioning

confidence: 99%

Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice

et al. 2007

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Aims/hypothesis Attempts to use an alternative source of islets to restore glucose homeostasis in diabetic patients require preclinical islet xenotransplantation models to be tested. These models raise questions about metabolic compatibility between species and the most appropriate metabolic parameters to be used to monitor graft function. The present study investigated and compared relevant gluco-metabolic parameters in pigs, monkeys and the pig-to-monkey islet transplantation model to gain insight into the potential clinical outcome of pig-to-human islet transplantation. Methods Basal and IVGTT-stimulated blood glucose, Cpeptide, insulin and glucagon levels were assessed in nondiabetic pigs and monkeys. The same parameters were used to evaluate the performance of porcine islet xenografts in diabetic monkeys. Results Non-diabetic cynomolgus monkeys showed lower levels of fasting and stimulated blood glucose but higher levels of C-peptide and insulin than non-diabetic pigs. The reported levels in humans lie between those of monkeys and pigs, and differences in metabolic parameters between pigs and humans appear to be smaller than those between pigs and cynomolgus monkeys. The transplantation data indicated that the degree of graft function (evaluated by the measurement of C-peptide levels) necessary to normalise blood glucose in the recipient was determined by the recipient levels rather than by the donor levels. Conclusions/interpretation The differences between donor and recipient species may affect the transplantation outcome and need to be considered when assessing graft function in xenotransplantation models. Given the differences between monkeys and humans as potential recipients of pig islets, it should be easier to reach glucose homeostasis in pig-to-human than in pig-to-non-human primate islet xenotransplantation.

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INDUCTION, MAINTENANCE, AND REVERSAL OF STREPTOZOTOCIN-INDUCED INSULIN-DEPENDENT DIABETES MELLITUS IN THE JUVENILE CYNOMOLGUS MONKEY (Macaca fascilularis)1

Abstract: IDDM can be consistently induced and safely treated in juvenile cynomolgus monkeys. Chronic vascular access can be maintained with minimal supervision and complications. This model is appropriate for studies investigating potential treatments for IDDM including islet cell transplantation.

Cited by 52 publications

References 14 publications

Successful Reversal of Streptozotocin-Induced Diabetes With Stable Allogeneic Islet Function in a Preclinical Model of Type 1 Diabetes

Successful Reversal of Streptozotocin-Induced Diabetes With Stable Allogeneic Islet Function in a Preclinical Model of Type 1 Diabetes

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

Metabolic aspects of pig-to-monkey (Macaca fascicularis) islet transplantation: implications for translation into clinical practice

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