Human immune system development and rejection of human islet allografts in spontaneously diabetic NOD-Rag1null IL2rgammanull Ins2Akita mice
Authors
Brehm, Michael A.Bortell, Rita
Diiorio, Philip J.
Leif, Jean H.
Laning, Joseph
Cuthbert, Amy
Yang, Chaoxing
Herlihy, Mary
Burzenski, Lisa M.
Gott, Bruce
Foreman, Oded
Powers, Alvin C.
Greiner, Dale L.
Shultz, Leonard D.
UMass Chan Affiliations
Department of Obstetrics and GynecologyProgram in Molecular Medicine
Department of Medicine, Division of Diabetes
Document Type
Journal ArticlePublication Date
2010-09-24Keywords
Adaptive ImmunityAnimals
Blood Glucose
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Crosses, Genetic
Flow Cytometry
Humans
Immunity, Innate
Interleukin Receptor Common gamma Subunit
Islets of Langerhans Transplantation
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, SCID
Mutation
Transplantation, Heterologous
Transplantation, Homologous
Obstetrics and Gynecology
Metadata
Show full item recordAbstract
OBJECTIVE: To create an immunodeficient mouse model that spontaneously develops hyperglycemia to serve as a diabetic host for human islets and stem cell-derived beta-cells in the absence or presence of a functional human immune system. RESEARCH DESIGN AND METHODS: We backcrossed the Ins2(Akita) mutation onto the NOD-Rag1(null) IL2rgamma(null) strain and determined 1) the spontaneous development of hyperglycemia, 2) the ability of human islets, mouse islets, and dissociated mouse islet cells to restore euglycemia, 3) the generation of a human immune system following engraftment of human hematopoietic stem cells, and 4) the ability of the humanized mice to reject human islet allografts. RESULTS: We confirmed the defects in innate and adaptive immunity and the spontaneous development of hyperglycemia conferred by the IL2rgamma(null), Rag1(null), and Ins2(Akita) genes in NOD-Rag1(null) IL2rgamma(null) Ins2(Akita) (NRG-Akita) mice. Mouse and human islets restored NRG-Akita mice to normoglycemia. Insulin-positive cells in dissociated mouse islets, required to restore euglycemia in chemically diabetic NOD-scid IL2rgamma(null) and spontaneously diabetic NRG-Akita mice, were quantified following transplantation via the intrapancreatic and subrenal routes. Engraftment of human hematopoietic stem cells in newborn NRG-Akita and NRG mice resulted in equivalent human immune system development in a normoglycemic or chronically hyperglycemic environment, with >50% of engrafted NRG-Akita mice capable of rejecting human islet allografts. CONCLUSIONS: NRG-Akita mice provide a model system for validation of the function of human islets and human adult stem cell, embryonic stem cell, or induced pluripotent stem cell-derived beta-cells in the absence or presence of an alloreactive human immune system.Source
Diabetes. 2010 Sep;59(9):2265-70. Epub 2010 Jun 22. Link to article on publisher's siteDOI
10.2337/db10-0323Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42824PubMed ID
20570944Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.2337/db10-0323