Genetically Engineered Human Islets Protected From CD8-mediated Autoimmune Destruction In Vivo |
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Authors: | Arnaud Zaldumbide Gonnie Alkemade Françoise Carlotti Tatjana Nikolic Joana RF Abreu Marten A Engelse Anja Skowera Eelco J de Koning Mark Peakman Bart O Roep Rob C Hoeben Emmanuel JHJ Wiertz |
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Institution: | 1. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands;2. Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands;3. Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands;4. Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands;5. Department of Immunobiology, King''s College, London, UK;6. National Institute of Health Research Biomedical Research Centre at Guy''s and St Thomas’ NHS Foundation Trust and King''s College, London, UK;7. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands |
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Abstract: | Islet transplantation is a promising therapy for type 1 diabetes, but graft function and survival are compromised by recurrent islet autoimmunity. Immunoprotection of islets will be required to improve clinical outcome. We engineered human β cells to express herpesvirus-encoded immune-evasion proteins, “immunevasins.” The capacity of immunevasins to protect β cells from autoreactive T-cell killing was evaluated in vitro and in vivo in humanized mice. Lentiviral vectors were used for efficient genetic modification of primary human β cells without impairing their function. Using a novel β-cell–specific reporter gene assay, we show that autoreactive cytotoxic CD8+ T-cell clones isolated from patients with recent onset diabetes selectively destroyed human β cells, and that coexpression of the human cytomegalovirus-encoded US2 protein and serine proteinase inhibitor 9 offers highly efficient protection in vitro. Moreover, coimplantation of these genetically modified pseudoislets with β-cell–specific cytotoxic T cells into immunodeficient mice achieves preserved human insulin production and C-peptide secretion. Collectively, our data provide proof of concept that human β cells can be efficiently genetically modified to provide protection from killing mediated by autoreactive T cells and retain their function in vitro and in vivo. |
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