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Biomaterials. 2019 Feb;192:271-281. doi: 10.1016/j.biomaterials.2018.11.015. Epub 2018 Nov 13.

Localized immune tolerance from FasL-functionalized PLG scaffolds.

Author information

1
Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
2
Institute of Cellular Therapeutics, Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA.
3
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
4
Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA; Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA.
5
Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. Electronic address: ldshea@umich.edu.
6
Institute of Cellular Therapeutics, Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA. Electronic address: haval.shirwan@louisville.edu.

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.

KEYWORDS:

Allogeneic; FasL; Immune tolerance; Islet transplantation; PLG; Polymer scaffold

PMID:
30458362
PMCID:
PMC6331284
[Available on 2020-02-01]
DOI:
10.1016/j.biomaterials.2018.11.015

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