Dept. of Pathology and Laboratory Medicine/ and Dept. of Surgery
Child and Family Research Institute, University of British Columbia
Transplantation of alginate-based microencapsulated neonatal porcine islets in diabetes.
Azadeh Hosseini-Tabatabaei1,5,6, Derek Dai1,5,6, Bassem Salama2, Blanche Lo3, Scott Patterson6, René Pedroza3,4, Karen Seeberger2, Megan Levings6, James Piret3,4, Greg Korbutt2, Bruce Verchere1,5,6.
1Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; 2Surgery, University of Alberta, Edmonton, AB, Canada; 3Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada; 4Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, Canada; 5Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada; 6Surgery, University of British Columbia, Vancouver, BC, Canada
Background: Transplantation of pancreatic beta cells has become a promising strategy to replace loss of insulin secretion in type 1 diabetes. Like any organ transplantation, this procedure faces several challenges, including shortage of islet donors and need for life-long immunosuppressive therapies. Using xenogeneic islets could address the need for donor tissue, although host immune responses towards xenogeneic tissue is a major drawback. We engineered alginate-based microcapsules to provide a semi-permeable barrier to protect neonatal porcine islets (NPIs) against xenograft rejection while allowing maintenance of euglycemia in a humanized mouse model of islet transplantation.
Methods: NPIs were microencapsulated using two formulations of alginate via extrusion/external gelation or emulsification/internal gelation. Immune-deficient (NOD-scid gamma; NSG) or NSG.B2M mice were rendered diabetic by injection of streptozotocin and 3000 NPIs were transplanted either intraperitoneally (encapsulated NPIs) or in the renal capsule (non-encapsulated NPIs). Blood glucose, weight, C-peptide levels were measured. To confirm maturation and functionality of NPI, intraperitoneal glucose tolerance tests and histology were performed. Animals received a single injection of human peripheral blood mononuclear cells (hPBMCs) or PBS (control mice) around day 155 post transplant and followed for development of diabetes and graft versus host disease (GvHD).
Results: NPIs matured and were functional as early as 2 months post transplantation as confirmed by insulin immunostaining, porcine C-peptide levels, and glucose tolerance. Both alginate bead formulations resulted in improved euglycemic control and islet graft survival compared to non-encapsulated islets that was sustained for at least 250 days. Mice that received hPBMCs to induce xenorejection remained euglycemic until the development of GvHD.
Conclusions: Alginate-based microencapsulation of neonatal porcine islets NPI may prolong islet graft function and slow xenorejection by human PBMCs.
Juvenile Diabetes Research Foundation. Child and Family Research Institute.
11:00 - 12:30
|Islet Xenotransplantation||Transplantation of alginate-based microencapsulated neonatal porcine islets in diabetes.||Room 109|