Xenografted Islet Cell Clusters From INSLEA29Y Transgenic Pigs Rescue Diabetes and Prevent Immune Rejection in Humanized Mice
- Nikolai Klymiuk1,
- Lelia van Buerck2,
- Andrea Bähr1,
- Monika Offers2,
- Barbara Kessler1,
- Annegret Wuensch1,
- Mayuko Kurome1,
- Michael Thormann3,
- Katharina Lochner2,
- Hiroshi Nagashima4,
- Nadja Herbach5,
- Rüdiger Wanke5,
- Jochen Seissler2 and
- Eckhard Wolf1⇓
- 1Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität, Munich, Germany
- 2Diabetes Zentrum, Medizinische Klinik Campus Innenstadt, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany
- 3Department of Cardiac Surgery, Ludwig-Maximilians-Universität, Munich, Germany
- 4Laboratory of Developmental Engineering, Meiji University, Kawasaki, Japan
- 5Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität Munich, Germany
- Corresponding authors: Eckhard Wolf, , and Jochen Seissler, .
N.K., L.v.B., J.S., and E.W. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1325/-/DC1.
See accompanying commentary, p. 1348.
- Received September 23, 2011.
- Accepted January 28, 2012.
- © 2012 by the American Diabetes Association.
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