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- Title
Human Immune System Development and Rejection of Human Islet Allografts in Spontaneously Diabetic NOD-Rag1<sup>null</sup> IL2rγ<sup>null</sup> Ins2<sup>Akita</sup> Mice.
- Authors
Brehm, Michael A.; Bortell, Rita; diIorio, Philip; Leif, Jean; Laning, Joseph; Cuthbert, Amy; Chaoxing Yang; Herlihy, Mary; Burzenski, Lisa; Gott, Bruce; Foreman, Oded; Powers, Alvin C.; Greiner, Dale L.; Shultz, Leonard D.
- Abstract
OBJECTIVE--To create an immunodeficient mouse model that spontaneously develops hyperglycemia to serve as a diabetic host for human islets and stem cell-derived B-cells in the absence or presence of a functional human immune system. RESEARCH DESIGN AND METHODS--We backcrossed the Ins2[sup Akita] mutation onto the NOD-Rag1[sup null] IL2rγ[sup 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 IL2rγ[sup null], Rag1[sup null], and Ins2[sup Akita] genes in NOD-Rag1[sup null] IL2rγ[sup null] Ins2[sup 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 IL2rγ[sup 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 Z-cells in the absence or presence of an alloreactive human immune system. Diabetes 59:2265-2270, 2010
- Publication
Diabetes, 2010, Vol 59, Issue 9, p2265
- ISSN
0012-1797
- Publication type
Academic Journal
- DOI
10.2337/db10-0323