Long‐term engraftment following transplantation of pig pancreatic primordia into non‐immunosuppressed diabetic rhesus macaques

Rogers, Sharon A.; Chen, Feng; Talcott, Mike; Faulkner, C.B.; Thomas, Judith M.; Thevis, Mario; Hammerman, Marc R.

doi:10.1111/j.1399-3089.2007.00429.x

Cited by 49 publications

(106 citation statements)

References 33 publications

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“…However, the immune suppression required to maintain the implants was either too toxic or included anti-CD40L, which cannot be used in human patients due to its thrombotic properties. Other studies suggested that E28 pancreatic tissue might be accepted in nonimmunosuppressed rats (33) and monkeys (34). In contrast, our mouse (9) and rat (35) data has revealed fierce rejection of pig embryonic tissue of any gestational time point in the absence of immune suppression, while demonstrating that the immunogenicity of E42 tissue was relatively lower compared to tissues harvested at E56 or beyond (9).…”

Section: Discussioncontrasting

confidence: 50%

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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Section: Discussioncontrasting

confidence: 50%

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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“…The severity of humoral rejection due to preexisting natural antibodies effectively precludes the use of non-transgenic swine as whole organ (pancreas) donors in primate hosts. [1][2][3][4][5][6][7][8][9] However, isolated cells such as islets of Langerhans (islets) can be transplanted into humans 6 or non-human primates 7,8 without initiating humoral rejection. Recent experience with pig to primate islet, 7 neonatal islet, 8 or hCD46 transgenic pig islet 9 transplantation shows that sustained insulin independence can be achieved, but unfortunately only through the use of immune suppressive agents that are not approved for humans or would result in an unacceptable level of morbidity.…”

Section: Organogenetic Tolerancementioning

confidence: 99%

“…[10][11][12][13] Cells originating from E28 pig pancreatic primordia engraft similarly in non immune-suppressed STZ-diabetic rhesus macaques. 3 Glucose tolerance can be nearly normalized in non-immunesuppressed diabetic rhesus macaques following transplantation of E28 pig pancreatic primordia (Fig. 1).…”

mentioning

confidence: 99%

“…In the case of embryonic pancreas, exocrine pancreatic tissue does not differentiate following transplantation, obviating complications that can result from exocrine components such as the enzymatic autodigestion of host tissues. The finding that it is possible to transplant pig pancreatic primordia to non-human primates with no immunosuppression requirements 3 is very important because it establishes the potential for transplantation in humans with no complications of immunosuppressive therapy.…”

mentioning

confidence: 99%

“…Extrapolating, it would take 100-160 primordia to render a diabetic rhesus macaque independent of exogenous insulin. This would require the sacrifice of about 7-12 pregnant sows and multiple surgeries 3 with the attendant complications.…”

mentioning

confidence: 99%

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Organogenetic tolerance

Hammerman

2010

Organogenesis

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Use of rat segmental intestine for fetal pancreatic transplantation

et al. 2010

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It is thought that the small intestine may provide a scaffold for pancreas regeneration. Herein, we investigated whether fetal pancreatic tissue could be transplanted into the segmental intestine in rats. Fetal pancreases from firefly luciferase transgenic Lewis rat embryos (embryonic day 14.5 and 15.5) were transplanted into streptozotocin (STZ)-induced diabetic wild-type Lewis rats. As a scaffold for pancreatic development, rat small intestinal segments were utilized after the removal of mucosa, and fetal pancreases were grafted into the luminal surface through the stoma. We also transplanted fetal pancreases into the omentum. The survival of transplanted fetal pancreases was monitored by luciferase-derived photons and blood glucose levels. Transplanted fetal pancreas-derived photons were stable for 28 days, suggesting that transplanted fetal pancreatic tissues survived and that their intestinal blood supply was maintained.

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Long‐term engraftment following transplantation of pig pancreatic primordia into non‐immunosuppressed diabetic rhesus macaques

Cited by 49 publications

References 33 publications

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

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

Organogenetic tolerance

Use of rat segmental intestine for fetal pancreatic transplantation

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