Localized immune tolerance from FasL-functionalized PLG scaffolds.

Abstract

Intraportal allogeneic islet transplantation has been demonstrated as a potential therapy for type 1 diabetes (T1D). The placement of islets into the liver and chronic immunosuppression to control rejection are two major limitations of islet transplantation. We hypothesize that localized immunomodulation with a novel form of FasL chimeric with streptavidin, SA-FasL, can provide protection and long-term function of islets at an extrahepatic site in the absence of chronic immunosuppression. Allogeneic islets modified with biotin and engineered to transiently display SA-FasL on their surface showed sustained survival following transplantation on microporous scaffolds into the peritoneal fat in combination with a short course (15 days) of rapamycin treatment. The challenges with modifying islets for clinical translation motivated the modification of scaffolds with SA-FasL as an off-the-shelf product. Poly (lactide-co-glycolide) (PLG) was conjugated with biotin and fabricated into particles and subsequently formed into microporous scaffolds to allow for rapid and efficient conjugation with SA-FasL. Biotinylated particles and scaffolds efficiently bound SA-FasL and induced apoptosis in cells expressing Fas receptor (FasR). Scaffolds functionalized with SA-FasL were subsequently seeded with allogeneic islets and transplanted into the peritoneal fat under the short-course of rapamycin treatment. Scaffolds modified with SA-FasL had robust engraftment of the transplanted islets that restored normoglycemia for 200 days. Transplantation without rapamycin or without SA-FasL did not support long-term survival and function. This work demonstrates that scaffolds functionalized with SA-FasL support allogeneic islet engraftment and long-term survival and function in an extrahepatic site in the absence of chronic immunosuppression with significant potential for clinical translation.

• Authors: Michael Skoumal, Kyle B Woodward, Hong Zhao, Feng Wang, Esma S Yolcu, Ryan M Pearson, Kevin R Hughes, Andrés J García, Lonnie D Shea, Haval Shirwan
• Journal: Biomaterials (Biomaterials) Vol. 192 Pg. 271-281 (02 2019) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 30458362 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Fas Ligand Protein
• Immobilized Proteins
• Recombinant Proteins
• Polylactic Acid-Polyglycolic Acid Copolymer
• Streptavidin

Topics

• Animals
• Fas Ligand Protein (immunology)
• Graft Survival
• Immobilized Proteins (immunology)
• Immune Tolerance
• Islets of Langerhans (immunology)
• Islets of Langerhans Transplantation (immunology, methods)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Polylactic Acid-Polyglycolic Acid Copolymer (chemistry)
• Recombinant Proteins (immunology)
• Streptavidin (immunology)
• Tissue Scaffolds (chemistry)