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

  1. Eckhard Wolf1
  1. 1Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, Munich, Germany
  2. 2Diabetes Zentrum, Medizinische Klinik Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany
  3. 3Department of Cardiac Surgery, Ludwig-Maximilians-Universität, Munich, Germany
  4. 4Laboratory of Developmental Engineering, Meiji University, Kawasaki, Japan
  5. 5Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität Munich, Germany
  1. Corresponding authors: Eckhard Wolf, ewolf{at}lmb.uni-muenchen.de, and Jochen Seissler, Jochen.seissler{at}med.uni-muenchen.de.

Abstract

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 IL2Rγnull mice. Cloned LEA-tg pigs are healthy and exhibit a strong β-cell–specific transgene expression. LEA-tg ICCs displayed the same potential to normalize glucose homeostasis as wild-type ICCs after transplantation. After adoptive transfer of human peripheral blood mononuclear cells, transplanted LEA-tg ICCs were completely protected from rejection, whereas reoccurrence of hyperglycemia was observed in 80% of mice transplanted with wild-type ICCs. In the current study, we provide the first proof-of-principle report on transgenic pigs with β-cell–specific expression of LEA29Y and their successful application as donors in a xenotransplantation model. This approach may represent a major step toward the development of a novel strategy for pig-to-human islet transplantation without side effects of systemic immunosuppression.

  • Received September 23, 2011.
  • Accepted January 28, 2012.

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  1. Diabetes
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