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

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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Fig. 1: Microgels for controlled presentation of immunomodulatory proteins.
Fig. 2: Microgels prolong SA-FasL retention in vivo.
Fig. 3: Survival of allogeneic islet grafts co-transplanted with SA-FasL-presenting microgels.
Fig. 4: Immune monitoring and the role of CD4+CD25+FoxP3+ Treg cells in islet graft acceptance.
Fig. 5: Treg cells are required for islet graft acceptance.
Fig. 6: Immune acceptance of allogeneic islet grafts co-transplanted with SA-FasL-presenting microgels in the epididymal fat pad.

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Acknowledgements

This work was funded in part by the Juvenile Diabetes Research Foundation (2-SRA-2014-287-Q-R) and NIH (R21EB020107, R21AI113348, R56AI121281 and U01AI132817). Funding from the NIH Innovation and Leadership in Engineering Technologies and Therapies Postdoctoral Training (T90 DK097787 to M.M.C.), a JDRF Postdoctoral Fellowship (to J.D.W.), the NIH Ruth L. Kirschstein National Research Service Award (F30AR069472 to C.T.J.) and a National Science Foundation Graduate Fellowship (to M.D.H.) is greatly appreciated. We thank the core facilities at the Parker H. Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology for use of, and assistance with, shared equipment, services and expertise.

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D.M.H. and M.M.C. synthesized and characterized the SA-FasL-presenting microgels. C.T.J. and M.D.H. performed the in vivo SA-FasL retention studies. D.M.H., K.B.W., M.M.C., J.D.W., H.Z., P.S. and M.T. performed the islet isolation and transplantation studies. W.S.B. produced and qualified the SA-FasL protein. K.B.W., P.S. and E.S.Y. performed the immune profiling analyses. A.J.G., L.S., E.S.Y. and H.S. conceived and designed all the experiments. D.M.H., M.M.C., E.S.Y., A.J.G. and H.S. wrote the manuscript.

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Correspondence to Andrés J. García or Haval Shirwan.

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Competing interests

H.S. and E.S.Y. hold equity in FasCure Therapeutics, which has an option to license the SA-FasL technology from the University of Louisville. A patent application (US 62,469,802) titled ‘FasL-engineered biomaterials with immunomodulatory function’, listing A.J.G., H.S., E.S.Y., D.M.H. and H.Z., was submitted on 9 March 2018 by the University of Louisville and Georgia Tech Research Corporation based on the results described in this manuscript.

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Headen, D.M., Woodward, K.B., Coronel, M.M. et al. Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance. Nature Mater 17, 732–739 (2018). https://doi.org/10.1038/s41563-018-0099-0

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