Date: Monday, June 13, 2016
Session Name: Concurrent Session: Xenotransplantation: Animal Models
Session Time: 4:30pm-6:00pm
Presentation Time: 5:18pm-5:30pm
Location: Room 102
Introduction: We have recently demonstrated that allogeneic islets engineered to transiently display on their surface a novel form of FasL protein chimeric with streptavidin (SA-FasL) induce tolerance in allogeneic mouse models. In this study, we tested the efficacy of this approach in inducing tolerance to porcine islets transplanted into mice using two different transplant sites; subrenal and intraportal.
Methods: Porcine islets were modified with 5 [micro]M biotin and engineered with SA-FasL protein (~200 ng/1000 islets). SA-FasL-engineered islets were transplanted under the kidney capsule (~2000 islets/transplant) or intraportally (2,500 islets/transplant) in streptozotocin diabetic C57BL/6 mice under a transient cover (20 days) of rapamycin. Unmodified pancreatic islets with rapamycin treatment served as controls.
Results: Porcine islets were effectively engineered with SA-FasL protein without a detrimental effect on their viability and function. SA-FasL-engineered islets induced apoptosis in responding mouse T cells in in vitro co-culture experiments. All control grafts with transient rapamycin treatment were rejected within 30 days post-transplantation. In marked contrast, all SA-FasL-engineered porcine grafts showed prolongation and ~60% of intraportal (n=37) and ~80% of subrenal (n=22) grafts survived for a 300-day observation period. Intraperitoneal glucose tolerance test demonstrated normal function of long-term islets, with the subrenal model performing better than the intraportal model. There was no detectable signs of acute or chronic toxicity of the procedure. The long-term euglycemia was due to the transplanted porcine islets as the surgical removal of the grafts resulted in prompt hyperglycemia.
Conclusion: SA-FasL as an immunomodulatory molecule is effective in inducing tolerance to porcine islet grafts transplanted subrenally as a standard site in rodents and intraportally as a clinically applicable yet immunologically more challenging site.
CITATION INFORMATION: Zhao H, Woodward K, Shirwan H, Graham M, Hering B, Yolcu E. Porcine Islets Engineered to Display SA-FasL Protein on Their Surface Induce Tolerance in Mice Following Transplantation into the Liver or Under the Kidney Capsule. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Zhao H, Woodward K, Shirwan H, Graham M, Hering B, Yolcu E. Porcine Islets Engineered to Display SA-FasL Protein on Their Surface Induce Tolerance in Mice Following Transplantation into the Liver or Under the Kidney Capsule. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/porcine-islets-engineered-to-display-sa-fasl-protein-on-their-surface-induce-tolerance-in-mice-following-transplantation-into-the-liver-or-under-the-kidney-capsule/. Accessed October 24, 2020.
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