Genetically Engineered Human Islets Protected From CD8-mediated Autoimmune Destruction In Vivo

摘要: 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 express herpesvirus-encoded immune-evasion proteins, “immunevasins.” The capacity immunevasins protect from autoreactive T-cell killing was evaluated in vitro vivo humanized mice. Lentiviral vectors were used efficient genetic modification primary without impairing their function. Using novel β-cell–specific reporter gene assay, we show that cytotoxic CD8+ clones isolated patients with recent onset diabetes selectively destroyed cells, coexpression the cytomegalovirus-encoded US2 protein serine proteinase inhibitor 9 offers highly protection vitro. Moreover, coimplantation these genetically modified pseudoislets T into immunodeficient mice achieves preserved insulin production C-peptide secretion. Collectively, our data provide proof concept can efficiently mediated retain vivo.