Xenografted Islet Cell Clusters From INSLEA29Y Transgenic Pigs Rescue Diabetes and Prevent Immune Rejection in Humanized Mice

Islet transplantation is a potential treatment for type 1 diabetes, but the shortage of donor organs limits its routine application. As potential donor animals, we generated transgenic pigs expressing LEA29Y, a high-affinity variant of the T-cell costimulation inhibitor CTLA-4Ig, under the control of the porcine insulin gene promoter. Neonatal islet cell clusters (ICCs) from INSLEA29Y transgenic (LEA-tg) pigs and wild-type controls were transplanted into streptozotocin-induced hyperglycemic NOD-scid IL2Rgnull mice. Cloned LEA-tg pigs are healthy and exhibit a strong b-cell–specific transgene expression. LEA-tg ICCs displayed the same potential to normalize glucose homeostasis as wild-type ICCs after transplan-tation. After adoptive transfer of human peripheral blood mononu-clear cells, transplanted LEA-tg ICCs were completely protected from rejection, whereas reoccurrence of hyperglycemia was ob-served in 80 % of mice transplanted with wild-type ICCs. In th