Localized immune tolerance from FasL-functionalized PLG scaffolds
- Resource Type
- Authors
- Kyle B. Woodward; Andrés J. García; Lonnie D. Shea; Feng Wang; Haval Shirwan; Ryan M. Pearson; Hong Zhao; Michael Skoumal; Esma S. Yolcu; Kevin R. Hughes
- Source
- Subject
- endocrine system
Fas Ligand Protein
medicine.medical_treatment
Biophysics
Islets of Langerhans Transplantation
Bioengineering
02 engineering and technology
Fas ligand
Article
Immune tolerance
Biomaterials
03 medical and health sciences
Islets of Langerhans
Polylactic Acid-Polyglycolic Acid Copolymer
medicine
Immune Tolerance
Animals
030304 developmental biology
0303 health sciences
geography
Mice, Inbred BALB C
geography.geographical_feature_category
Tissue Scaffolds
Chemistry
Graft Survival
Immunosuppression
021001 nanoscience & nanotechnology
Fas receptor
Islet
Recombinant Proteins
Transplantation
Mice, Inbred C57BL
Immobilized Proteins
Mechanics of Materials
Apoptosis
Biotinylation
Ceramics and Composites
Cancer research
Streptavidin
0210 nano-technology
- Language
- English
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.