Cited by 175Pancreatic function and diabetesDiabetes and associated disordersT-cell and B-cell Immunology

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Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance

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Headen, Devon M., Woodward, Kyle B., Coronel, María M., Shrestha, Pradeep, Weaver, Jessica D., Zhao, Hong, Tan, Min, Hunckler, Michael D., Bowen, William S., Johnson, Christopher T., Shea, Lonnie, Yolcu, Esma S., García, Andrés J., Shirwan, Haval·2018·Nature Materials

DOI 10.1038/s41563-018-0099-0PMC PMC6060019

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Abstract

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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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: Woodward, Kyle B.
Coronel, María M.
Shrestha, Pradeep
Weaver, Jessica D.
Zhao, Hong
Hunckler, Michael D.
Bowen, William S.
Johnson, Christopher T.
Shea, Lonnie
Yolcu, Esma S.
García, Andrés J.
Shirwan, Haval
Venue: Nature Materials
Publisher: Springer Science and Business Media LLC
Published: 2018-06-04
Volume: 17
Issue: 8
Pages: 732-739
ISSN: 1476-1122 (ISSN-L)
1476-4660
DOI: 10.1038/s41563-018-0099-0
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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 › Endocrinology, Diabetes and Metabolism › 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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Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance

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