Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance
Open accessAbstract
Islet transplantation is a promising therapy for type 1 diabetes. However, chronic immunosuppression to control rejection of allogeneic islets induces morbidities and impairs islet function. T effector cells are responsible for islet allograft rejection and express Fas death receptors following activation, becoming sensitive to Fas-mediated apoptosis. Here, we report that localized immunomodulation using microgels presenting an apoptotic form of the Fas ligand with streptavidin (SA-FasL) results in prolonged survival of allogeneic islet grafts in diabetic mice. A short course of rapamycin treatment boosted the immunomodulatory efficacy of SA-FasL microgels, resulting in acceptance and function of allografts over 200 days. Survivors generated normal systemic responses to donor antigens, implying immune privilege of the graft, and had increased CD4+CD25+FoxP3+ T regulatory cells in the graft and draining lymph nodes. Deletion of T regulatory cells resulted in acute rejection of established islet allografts. This localized immunomodulatory biomaterial-enabled approach may provide an alternative to chronic immunosuppression for clinical islet transplantation.
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PD-L1 or FasL proteins immobilized onto the surface of poly(ethylene glycol) microgels, mixed with allogeneic islets and co-transplanted into mice or non-human primates, in conjunction with a transient rapamycin treatment, greatly improved islet survival without the need for long-term immunosuppression or encapsulation.
“To this end, PD-L1111 or FasL112,113 proteins were immobilized onto the surface of poly(ethylene glycol) microgels, which were then mixed together with allogeneic islets and co-transplanted into either mice111,112 or non-human primates113. In conjunction with a transient rapamycin treatment, these functionalized microgels greatly improved islet survival without the need for long-term immunosuppres”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [112]
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Self-citation
- Authors
- Headen, D. M., Woodward, K. B., Coronel, M. M., Shrestha, P., Weaver, J. D., Zhao, H., Tan, M., Hunckler, M. D., Bowen, W. S., Johnson, C. T., Shea, L., Yolcu, E. S., García, A. J., & Shirwan, H.
- Affiliations
- Georgia Institute of Technology (US)
- University of Louisville (US)
- Corresponding author
- Shirwan, Haval
- ORCID
- Venue
- Nature Materials
- Published
- 2018-06-04
- Volume
- 17
- Issue
- 8
- Pages
- 732-739
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- PMC
- PMC6060019
- OpenAlex
- W2807344337
- Cited by
- 175
- References
- 44
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 29 · 2023: 27 · 2022: 24 · 2021: 25 · 2020: 16 · 2019: 23 · 2018: 7
- FWCI
- 18.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Materials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (4t90dk097787-05, 1s10od016264-01a1)
- National Institute of General Medical Sciences (T32GM008169)
- National Institute of Allergy and Infectious Diseases (R21AI113348, U01AI132817, R56AI121281)
- National Institute of Diabetes and Digestive and Kidney Diseases (T90-DK097787, P30DK020572)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (F30AR069472)
- National Institute of Biomedical Imaging and Bioengineering (R21EB020107)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- islet transplantation, type 1 diabetes, allograft rejection, Fas ligand, microgels, streptavidin, rapamycin, regulatory T cells, effector T cells, immune privilege, biomaterials, graft acceptance
- MeSH terms
- Animals, Biocompatible Materials, Transplantation, Homologous, Islets of Langerhans Transplantation, Streptavidin, Mice, Fas Ligand Protein, Immunomodulation
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