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

Abstract

Background: Transplantation therapy for human diabetes is limited by a shortage of donor organs, and transplant function diminished over time by cell death and limited potential for expansion of beta cells in pancreas or islets. Outcomes are complicated by immunosuppression. A way to overcome supply and expansion problems is to xenotransplant embryonic tissue. Previously, we have shown that beta cells originating from embryonic day (E) 28 (E28) pig pancreatic primordia transplanted into the mesentery of streptozotocin (STZ)-diabetic (type 1) Lewis rats or Zucker Diabetic Fatty (ZDF) diabetic (type 2) rats engraft and normalize glucose tolerance without the need for host immune-suppression.

Methods: In this study, we transplant E28 pig pancreatic primordia in the mesentery of STZ-diabetic rhesus macaques.

Results: Long-term engraftment of pig beta cells within liver, pancreas and mesenteric lymph nodes post-transplantation of E28 pig pancreatic primordia into STZ-diabetic rhesus macaques is demonstrated by electron microscopy, positive immune-histochemistry for insulin, and positive RT-PCR and in situ hybridization for porcine proinsulin mRNA. Insulin requirements were reduced in one macaque followed over 22 months post-transplantation and porcine insulin detected in plasma using sequential affinity chromatography, HPLC and mass spectrometry. Of potential importance for application of this transplantation technology to treatment of diabetes in humans and confirmatory of our previous findings in Lewis and ZDF rats, no host immunosuppression is required.

Conclusions: Under selected circumstances, pancreatic primordia elicit a muted immune response relative to more differentiated tissue, such that engraftment occurs in non-immunosuppressed hosts. Our findings that pig pancreatic primordia engraft long-term in non-immunosuppressed STZ-diabetic rhesus macaques establishes the potential for their use in human diabetics.