Human immune system development and rejection of human islet allografts in spontaneously diabetic NOD-Rag1null IL2rgammanull Ins2Akita mice
Department of Medicine, Division of Diabetes; Program in Molecular Medicine; Department of Obstetrics and Gynecology
Adaptive Immunity; Animals; 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
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.
DOI of Published Version
Diabetes. 2010 Sep;59(9):2265-70. Epub 2010 Jun 22. Link to article on publisher's site
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.; and Shultz, Leonard D., "Human immune system development and rejection of human islet allografts in spontaneously diabetic NOD-Rag1null IL2rgammanull Ins2Akita mice" (2010). Obstetrics and Gynecology Publications and Presentations. 4.