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.
Subscribe to Journal
Get full journal access for 1 year
only $16.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nakayama, M. et al. Priming and effector dependence on insulin B:9–23 peptide in NOD islet autoimmunity. J. Clin. Invest. 117, 1835–1843 (2007).
Roep, B. O., Arden, S. D., Devries, R. R. P. & Hutton, J. C. T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins. Nature 345, 632–634 (1990).
Yoon, J. W. et al. Control of autoimmune diabetes in NOD mice by CAD expression or suppression in beta cells. Science 284, 1183–1187 (1999).
Alejandro, R. et al. Long-term function (6 years) of islet allografts in type 1 diabetes. Diabetes 46, 1983–1989 (1997).
Boggi, U. et al. Long-term (5 years) efficacy and safety of pancreas transplantation alone in type 1 diabetic patients. Transplantation 93, 842–846 (2012).
Shapiro, A. M. J. et al. International trial of the Edmonton protocol for islet transplantation. N. Engl. J. Med. 355, 1318–1330 (2006).
Radu, R. G. et al. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity. Am. J. Physiol. Endocrinol. Metab. 288, E365–E371 (2005).
Hernandez-Fisac, I. et al. Tacrolimus-induced diabetes in rats courses with suppressed insulin gene expression in pancreatic islets. Am. J. Transplant. 7, 2455–2462 (2007).
Haskins, K. & McDuffie, M. Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T-cell clone. Science 249, 1433–1436 (1990).
Roep, B. O. et al. Auto- and alloimmune reactivity to human islet allografts transplanted into type 1 diabetic patients. Diabetes 48, 484–490 (1999).
Yolcu, E. S. et al. Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression. Immunol. Cell Biol. 86, 650–658 (2008).
Ju, S. T. et al. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373, 444–448 (1995).
Brunner, T. et al. Cell-autonomous Fas (CD95)/Fas–ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373, 441–444 (1995).
Arai, H., Chan, S. Y., Bishop, D. K. & Nabel, G. J. Inhibition of the alloantibody response by CD95 ligand. Nat. Med. 3, 843–848 (1997).
Lau, H. T., Yu, M., Fontana, A. & Stoeckert, C. J. Prevention of islet allograft rejection with engineered myoblasts expressing FasL in mice. Science 273, 109–112 (1996).
Matsue, H. et al. Induction of antigen-specific immunosuppression by CD95L cDNA-transfected ‘killer’ dendritic cells. Nat. Med. 5, 930–937 (1999).
Min, W. P. et al. Dendritic cells genetically engineered to express Fas ligand induce donor-specific hyporesponsiveness and prolong allograft survival. J. Immunol. 164, 161–167 (2000).
Tourneur, U. et al. Transgenic expression of CD95 ligand on thyroid follicular cells confers immune privilege upon thyroid allografts. J. Immunol. 167, 1338–1346 (2001).
O'Reilly, L. A. et al. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461, 659–663 (2009).
Ottonello, L., Tortolina, G., Amelotti, M. & Dallegri, F. Soluble Fas ligand is chemotactic for human neutrophilic polymorphonuclear leukocytes. J. Immunol. 162, 3601–3606 (1999).
Yolcu, E. S., Askenasy, N., Singh, N. P., Cherradi, S. E. & Shirwan, H. Cell membrane modification for rapid display of proteins as a novel means of immunomodulation: FasL-decorated cells prevent islet graft rejection. Immunity 17, 795–808 (2002).
Yolcu, E. S. et al. Pancreatic islets engineered with SA-FasL protein establish robust localized tolerance by inducing regulatory T cells in mice. J. Immunol. 187, 5901–5909 (2011).
Headen, D. M., Aubry, G., Lu, H. & García, A. J. Microfluidic-based generation of size-controlled, biofunctionalized synthetic polymer microgels for cell encapsulation. Adv. Mater. 26, 3003–3008 (2014).
Phelps, E. A. et al. Maleimide cross-linked bioactive PEG hydrogel exhibits improved reaction kinetics and cross-linking for cell encapsulation and in situ delivery. Adv. Mater. 24, 64–70 (2012).
Phelps, E. A., Headen, D. M., Taylor, W. R., Thule, P. M. & Garcia, A. J. Vasculogenic bio-synthetic hydrogel for enhancement of pancreatic islet engraftment and function in type 1 diabetes. Biomaterials 34, 4602–4611 (2013).
Yellen, P. et al. High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex 1 and suppressing phosphorylation of 4E-BP1. Cell Cycle 10, 3948–3956 (2011).
Zeiser, R. et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 111, 453–462 (2008).
Battaglia, M., Stabilini, A. & Roncarolo, M. G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–4748 (2005).
Basu, S., Golovina, T., Mikheeva, T., June, C. H. & Riley, J. L. Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J. Immunol. 180, 5794–5798 (2008).
Rao, R. R., Li, Q., Odunsi, K. & Shrikant, P. A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32, 67–78 (2010).
Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Hurez, V. et al. Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice. Aging Cell 14, 945–956 (2015).
Bunnag, S. et al. FOXP3 expression in human kidney transplant biopsies is associated with rejection and time post transplant but not with favorable outcomes. Am. J. Transplant 8, 1423–1433 (2008).
Yapici, U. et al. Intragraft FOXP3 protein or mRNA during acute renal allograft rejection correlates with inflammation, fibrosis, and poor renal outcome. Transplantation 87, 1377–1380 (2009).
Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).
Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63 (2007).
Baidal, D. A. et al. Bioengineering of an intraabdominal endocrine pancreas. N. Engl. J. Med. 376, 1887–1889 (2017).
Berman, D. M. et al. Bioengineering the endocrine pancreas: intraomental islet transplantation within a biologic resorbable scaffold. Diabetes 65, 1350–1361 (2016).
Weaver, J. D. et al. Vasculogenic hydrogel enhances islet survival, engraftment, and function in leading extrahepatic sites. Sci. Adv. 3, e1700184 (2017).
Stuart, P. M. et al. CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J. Clin. Invest. 99, 396–402 (1997).
Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R. & Ferguson, T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).
Takeda, Y. et al. Protection of islet allografts transplanted together with Fas ligand expressing testicular allografts. Diabetologia 41, 315–321 (1998).
Kang, S. M. et al. Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat. Med. 3, 738–743 (1997).
Ogasawara, J. et al. Lethal effect of the anti-Fas antibody in mice. Nature 364, 806–809 (1993).
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.
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.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Localized Immunomodulation with PD-L1 Results in Sustained Survival and Function of Allogeneic Islets without Chronic Immunosuppression
The Journal of Immunology (2020)
Journal of Biomedical Materials Research Part A (2020)
Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long‐term graft‐localized immune privilege
American Journal of Transplantation (2020)
Journal of Pharmaceutical Investigation (2020)
Bio‐Orthogonal, Site‐Selective Conjugation of Recombinant Proteins to Microporous Annealed Particle Hydrogels for Tissue Engineering
Advanced Therapeutics (2020)