Engraftment of Insulin-Producing Cells from Porcine Islets in Non-Immune-Suppressed Rats or Nonhuman Primates Transplanted Previously with Embryonic Pig Pancreas

Abstract

Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation (embryonic day 28 (E28)) engraft long-term in non-immune, suppressed diabetic rats or rhesus macaques. Morphologically, similar cells originating from adult porcine islets of Langerhans (islets) engraft in non-immune-suppressed rats or rhesus macaques previously transplanted with E28 pig pancreatic primordia. Our data are consistent with induction of tolerance to an endocrine cell component of porcine islets induced by previous transplantation of embryonic pig pancreas, a novel finding we designate organogenetic tolerance. The potential exists for its use to enable the use of pigs as islet cell donors for humans with no immune suppression requirement.

Generation of vascular chimerism within donor organs

“…It has been shown that following islet transplantation in mice, a progressive replacement of donor endothelial cells by the endothelial cells of recipient origin occurs, and that this type of endothelial chimerism play a role in protecting the islet grafts from humoral rejection 35 . This is further supported by earlier reports, describing the ability of avascular, embryonic kidneys 36 , 37 and pancreas 38 , 39 to attract host vasculature, rendering them less susceptible to humoral rejection 40 .…”

Islet xenotransplantation: what is the optimal age of the islet‐source pig?

“…Hammerman has advocated the use of embryonic pancreatic primordia over pluripotent embryonic stem cells or terminally differentiated pancreatic cells . Embryonic primordial tissue differentiates along a predetermined line into pancreatic tissue.…”

“…Unlike pluripotent stem cells, which need to be steered toward pancreatic differentiation, pancreatic primordia do not require the differentiation of pluripotent cells into pancreatic cells. Also, the risk of teratoma is greater when pluripotent stem cells are used . Following embryonic pancreas transplantation, the exocrine pancreatic tissue does not differentiate; thus, the immune response and inflammatory complications resulting from the exocrine component are absent.…”

“…Korbutt has discussed the different characteristics and applications of adult, neonatal, and fetal porcine islet-like cell clusters in xenotransplantation [32]. Embryonic pig islets and pancreatic primordia are also being explored for this purpose [33][34][35][36][37][38].…”

Xenotransplantation literature update, July–October 2011

“…Hammerman [3] discussed the potential of pig embryonic pancreatic primordia in islet xenotransplantation. The author concludes that transplantation of embryonic pancreatic primordia enables the subsequent engraftment of islet cells from differentiated adult tissue of the same organ, without the need for host immune suppression, a phenomenon termed organogenetic tolerance.…”