Local immunomodulation Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance.
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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 | Devon M Headen, Kyle B Woodward, María M Coronel, Pradeep Shrestha, Jessica D Weaver, Hong Zhao, Min Tan, Michael D Hunckler, William S Bowen, Christopher T Johnson, Lonnie Shea, Esma S Yolcu, Andrés J García, Haval Shirwan |
| Journal | Nature materials (Nat Mater) Vol. 17 Issue 8 Pg. 732-739 (08 2018) ISSN: 1476-4660 [Electronic] England |
| PMID | 29867165 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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