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Cited by 77Pancreatic function and diabetesDiabetes and associated disordersT-cell and B-cell Immunology

FasL microgels induce immune acceptance of islet allografts in nonhuman primates

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Lei, Ji, Coronel, María M., Yolcu, Esma S., Deng, Hongping, Grimany-Nuno, Orlando, Hunckler, Michael D., Ulker, Vahap, Yang, Zhihong +12 more·2022·Science Advances
DOI 10.1126/sciadv.abm9881PMC PMC9106299
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Abstract

Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)–FasL–presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3 + cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in β cell replacement for treating type 1 diabetes.

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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 [113]

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Authors
Lei, J., Coronel, M. M., Yolcu, E. S., Deng, H., Grimany-Nuno, O., Hunckler, M. D., Ulker, V., Yang, Z., Lee, K. M., Zhang, A., Luo, H., Peters, C. W., Zou, Z., Chen, T., Wang, Z., McCoy, C. S., Rosales, I. A., Markmann, J. F., Shirwan, H., & García, A. J.
Affiliations
  • Harvard University (US)
  • Georgia Institute of Technology (US)
  • University of Louisville (US)
  • University of Missouri (US)
  • Chengdu Military General Hospital (CN)
  • Xiamen University (CN)
  • Massachusetts Institute of Technology (US)
  • Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
Corresponding author
  • Lei, Ji
  • Coronel, María M.
  • Yolcu, Esma S.
  • Markmann, James F.
  • Shirwan, Haval
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-05-13
Volume
8
Issue
19
Pages
eabm9881-eabm9881
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.abm9881
PMC
PMC9106299
OpenAlex
W4280566781
Cited by
77
References
54
Citations by year
2026: 14 · 2025: 14 · 2024: 25 · 2023: 18 · 2022: 6
FWCI
15.05
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute of Allergy and Infectious Diseases (U01AI132817)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128840)
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, Foxp3+ regulatory T cells, rapamycin, graft survival, islet allograft rejection, beta cell replacement, non-human primates, immunosuppression-free transplantation, omental transplantation
MeSH terms
Microgels, Animals, Diabetes Mellitus, Type 1, Primates, Islets of Langerhans Transplantation, Streptavidin, Sirolimus, Allografts

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