Embryonic Pig Pancreatic Tissue Transplantation for the Treatment of Diabetes

Eventov‐Friedman, Smadar; Tchorsh, Dalit; Katchman, Helena; Shezen, Elias; Aronovich, Anna; Hecht, Gil; Dekel, Benjamin; Rechavi, Gideon; Blazar, Bruce R.; Feine, Ilan; Tal, Orna; Freud, Enrique; Reisner, Yaīr

doi:10.1371/journal.pmed.0030215

Cited by 57 publications

(72 citation statements)

References 64 publications

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“…2D). This observation emphasizes the long-term regenerative capability of the pancreatic tissue, in agreement with our previous mouse studies (9).…”

Section: Resultssupporting

confidence: 93%

“…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). Therefore, we proposed that mild immune suppression might suffice to permit engraftment and growth of the E42 embryonic tissue.…”

Section: Discussioncontrasting

confidence: 63%

“…We have shown recently in a mouse model that this outcome could be attributed, in part, to the relatively late stage of gestation at which the embryonic pancreatic tissue was harvested. Thus, based on growth potential and immunogenicity, we demonstrated that the optimal ''window'' for these transplants could be provided at around E42 (7,9).…”

Section: Discussionmentioning

confidence: 94%

“…Once this threshold was established, we were able to further characterize an optimal gestational window for transplantation based on growth potential and immunogenicity. Thus, while the optimal window for kidney transplantation was defined around E28, our data suggested E42 as the optimal gestational time point for pig donor tissue in pancreatic transplantation (9). Importantly, upon growth and development of the embryonic pancreatic implant, acini gradually disappear and the tissue is predominantly comprised of islets and stroma identified by vimentin straining.…”

mentioning

confidence: 80%

“…Importantly, upon growth and development of the embryonic pancreatic implant, acini gradually disappear and the tissue is predominantly comprised of islets and stroma identified by vimentin straining. Thus, the risk of potential ongoing destruction of the growing organ by local proteolytic enzymes, which might be released by the exocrine components of the implant, is miniml (9). These mouse studies also demonstrated the curative potential of such implants in diabetic mice under relatively tolerable immune suppression.…”

mentioning

confidence: 82%

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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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“…2D). This observation emphasizes the long-term regenerative capability of the pancreatic tissue, in agreement with our previous mouse studies (9).…”

Section: Resultssupporting

confidence: 93%

Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 80%

mentioning

confidence: 82%

See 3 more Smart Citations

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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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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A Role for Regulatory T Cells in Acceptance of ESC-Derived Tissues Transplanted Across an Major Histocompatibility Complex Barrier

et al. 2010

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We have previously reported that ESC-derived tissues are subject to some level of immune privilege, which might facilitate induction of immune tolerance. Herein, we further demonstrate that fully allogeneic ESC-derived tissues are accepted with a regimen of coreceptor blockade even in recipients known to be relatively resistant to such a tolerizing protocol. Moreover, ESC-derived tissues could be spontaneously accepted across a class I major histocompatibility complex disparity. We further show that CD4 1 FoxP3 1 regulatory T cells (Treg) appear to be essential for this natural ''privileged'' state as their ablation with an anti-CD25 mAb results in rejection of ESC-derived tissue. This same treatment exposes activation of macrophages and effector CD8 1 T cells, suggesting that these cells are subject to regulatory T cell control. Thus, spontaneous acceptance of ESCderived tissues mimics the acquired immune privilege induced by coreceptor blockade and is determined by Tregmediated suppression.

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Embryonic Pig Pancreatic Tissue Transplantation for the Treatment of Diabetes

Cited by 57 publications

References 64 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

Use of rat segmental intestine for fetal pancreatic transplantation

A Role for Regulatory T Cells in Acceptance of ESC-Derived Tissues Transplanted Across an Major Histocompatibility Complex Barrier

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