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ABSTRACT: The treatment of type I diabetes by islet cell transplantation, while promising, remains restricted due to the incomplete efficacy and toxicity associated with current immunosuppression, and by limited organ availability. Given reports suggesting bone marrow derived stem cell plasticity, we sought to determine whether such cells could give rise to pancreatic islet cells in vivo. In the context of autoimmune diabetes, we transplanted unfractionated bone marrow from beta-gal trangenic donor mice into NOD mice prior to, at, and two weeks beyond the onset of disease. Successful bone marrow engraftment before diabetes onset prevented disease in all mice and for 1 year after transplant. However, despite obtaining full hematopoietic engraftment in over 50 transplanted mice, only one mouse became insulin independent, and no beta-Gal positive islets were detected in any of the mice. To test whether tolerance to islets was achieved, we injected islets obtained from the same allogeneic donor strain as the hematopoietic cells into 4 transplant recipients, and 2 had a reversion of their diabetes. Thus allogeneic bone marrow transplantation prevents autoimmune diabetes and tolerizes the recipient to donor islet grants, even in diabetic animals, yet the capacity of bone marrow derived cells to differentiate into functional islet cells, at least without additional manipulation, is limited in our model.
Experimental Hematology 07/2005; 33(6):699-705. · 2.90 Impact Factor
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ABSTRACT: To develop and assess a technique for induction of C peptide-negative diabetes in adult nonhuman primates in preparation for preclinical investigation of type 1 diabetes treatments.
First, temporary embolization of the hepatic and gastric arteries was performed in 14 adult nonhuman primates (six cynomolgus, five rhesus, and three pigtail macaques). After embolization was confirmed with angiography, streptozotocin was injected at a dose of 50-70 mg/kg into the celiac artery and branches supplying the pancreas. The macaques then were given intravenous injections of arginine and glucose, and blood levels of insulin and C peptide were measured with an enzyme-linked immunosorbent assay to determine whether diabetes had been induced.
All but one of the macaques developed persistent long-term C peptide-negative diabetes after the streptozotocin injection. One macaque did not develop diabetes after the initial injection and was given a second dose of streoptozotocin, which did induce diabetes. None of the macaques showed any symptoms of hepatic or renal injury, and only one died (of gastric dilatation 5 days after the procedure).
Streptozotocin injection after temporary embolization of the hepatic and gastric arteries is a safe and reproducible method for inducing C peptide-negative diabetes in adult nonhuman primates in preparation for preclinical investigation of type 1 diabetes treatments.
Radiology 02/2004; 230(1):163-8. · 5.73 Impact Factor
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ABSTRACT: While islet cell transplantation is a promising way to restore insulin independence to patients with type I diabetes mellitus, a detailed histological analysis of the transplanted, intraportal islets has not yet been reported. Rhesus macaques underwent total pancreatectomy, then had allogeneic isolated islets infused into their portal vein, followed by daclizumab, tacrolimus, and sirolimus to prevent islet rejection. Islets were evenly distributed among the liver lobes. Liver sections from a primate given allogeneic islets 5 d earlier did not display any islet capillary formation, whereas intrahepatic islets transplanted 30 and 90 d before euthanasia showed an abundant capillary supply. Localized hepatocellular glycogenosis was observed surrounding the islets in a primate with functioning islets 7 months post transplant. Liver sections from a primate that rejected islets transplanted 2 months prior displayed only islet remnants with prominent local lymphohistiocytic inflammation and an occasional capillary. We conclude that islets develop an abundant vascular supply within 30 d following transplant and because capillaries persist even following rejection, that the vascular cells are likely from the recipient. While transplanted islets were not vascularized early post transplant, the primates remained insulin independent. The long-term consequence of islets in the liver, marked by the glycogenosis, remains unknown and warrants further study.
Journal of Clinical Endocrinology & Metabolism 01/2003; 87(12):5424-9. · 6.50 Impact Factor
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Boaz Hirshberg,
Sean Montgomery,
Michael G Wysoki,
He Xu,
Doug Tadaki,
Janet Lee,
Kenneth Hines,
Jason Gaglia, Noelle Patterson,
John Leconte,
Douglas Hale,
Richard Chang,
Alan D Kirk,
David M Harlan
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ABSTRACT: We've established a nonhuman primate islet allotransplant model to address questions such as whether transplanting islets into the gut's arterial system would more safely and as effectively support long-term islet allograft survival compared with the traditional portal vein approach. We reasoned that islets make up <2% of pancreatic cell mass but consume an estimated 20% of arterial blood flow, suggesting an advantage for the arterial site. Access to the arterial system is also easier and safer than the portal system. Pancreatectomized rhesus macaques were transplanted with allogeneic islets infused into either the portal vein (n = 6) or the celiac artery (n = 4). To prevent rejection, primates were given daclizumab, tacrolimus, and rapamycin. In five of six portal vein experiments, animals achieved normoglycemia without exogenous insulin. In contrast, none of the animals given intra-arterial islets showed even transient insulin independence (P = 0.048). Two of the latter animals received a second islet transplant, this time to the portal system, and both achieved insulin independence. Thus, intraportal islet transplantation under conventional immunosuppression is feasible in primates and can result in long-term insulin independence when adequate immunosuppression is maintained. Arterial islet injection, however, does not appear to be a viable islet transplantation technique.
Diabetes 08/2002; 51(7):2135-40. · 8.29 Impact Factor
