Human Immune System Development and Rejection of Human Islet Allografts in Spontaneously Diabetic NOD-Rag1null IL2rγ Ins2Akita Mice

Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Diabetes (Impact Factor: 8.1). 09/2010; 59(9):2265-70. DOI: 10.2337/db10-0323
Source: PubMed


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.
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.
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.
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.

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    • "Only recently have a few studies utilized the potential of the humanized mouse to understand the pathogenesis of autoimmune disease, such as type 1 diabetes [40]. Brehm and colleagues showed that human islet cells were capable of restoring normal glycemic levels in NSG-Akita mice and that human leukocytes derived from stem cells were capable of rejecting human islet allographs [41]. Further, injection of peripheral blood mononuclear cells from SLE patients into BalbRag2−/−IL2rγnull mice led to autoantibody production and increased mortality as compared to injection of cells from control patients [42]. "
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