title: Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice.
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 IL2Rγ(null) 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.
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Klymiuk
authors.forename: Lelia
authors.initials: L
authors.lastname: van Buerck
authors.forename: Andrea
authors.initials: A
authors.lastname: Bähr
authors.forename: Monika
authors.initials: M
authors.lastname: Offers
authors.forename: Barbara
authors.initials: B
authors.lastname: Kessler
authors.forename: Annegret
authors.initials: A
authors.lastname: Wuensch
authors.forename: Mayuko
authors.initials: M
authors.lastname: Kurome
authors.forename: Michael
authors.initials: M
authors.lastname: Thormann
authors.forename: Katharina
authors.initials: K
authors.lastname: Lochner
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagashima
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Wanke
authors.forename: Jochen
authors.initials: J
authors.lastname: Seissler
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000601:surgery*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006943:Hyperglycemia / Q000235:genetics / Q000276:immunology / Q000601:surgery; D007328:Insulin / Q000235:genetics; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D011401:Promoter Regions, Genetic; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D007328:Insulin