Journal
NATURE MATERIALS
Volume 17, Issue 8, Pages 732-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41563-018-0099-0
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Funding
- Juvenile Diabetes Research Foundation [2-SRA-2014-287-Q-R]
- NIH [R21EB020107, R21AI113348, R56AI121281, U01AI132817]
- NIH Innovation and Leadership in Engineering Technologies and Therapies Postdoctoral Training [T90 DK097787]
- JDRF Postdoctoral Fellowship
- NIH Ruth L. Kirschstein National Research Service Award [F30AR069472]
- National Science Foundation
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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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