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

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. +6 more·2018·Nature Materials

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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  • 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”

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Research works printed but not linked: 3

  1. [26]Ju ST Panka DJ Cui H Ettinger R el-Khatib M Sherr DH Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation Nature 1995 373 6513 444 448 7530337
  2. [28]Lau HT Yu M Fontana A Stoeckert CJ Jr Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice Science 1996 273 109 112 8658177
  3. [45]Yolcu ES Zhao H Bandura-Morgan L Lacelle C Woodward KB Askenasy N Pancreatic Islets Engineered with SA-FasL Protein Establish Robust Localized Tolerance by Inducing Regulatory T Cells in Mice J Immunol 2011 187 11 5901 5909 22068235 PMC3232043

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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
Venue
Nature Materials
Published
2018-06-04
Volume
17
Issue
8
Pages
732-739
ISSN
  • 1476-1122 (ISSN-L)
  • 1476-4660
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
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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