Human Immune System Development and Rejection of Human Islet Allografts in Spontaneously Diabetic NOD-Rag1null IL2rγnull Ins2Akita Mice

被引：61

作者：

Brehm, Michael A. ^{[1
]}

Bortell, Rita ^{[1
]}

diIorio, Philip ^{[1
]}

Leif, Jean ^{[1
]}

Laning, Joseph ^{[1
]}

Cuthbert, Amy ^{[1
]}

Yang, Chaoxing ^{[1
]}

Herlihy, Mary ^{[2
]}

Burzenski, Lisa ^{[3
]}

Gott, Bruce ^{[3
]}

Foreman, Oded ^{[3
]}

Powers, Alvin C. ^{[4
,5
]}

Greiner, Dale L. ^{[1
,3
,6
]}

Shultz, Leonard D. ^{[3
]}

机构：

[1] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA

[2] Univ Massachusetts, Mem Med Ctr, Worcester, MA USA

[3] Jackson Lab, Bar Harbor, ME 04609 USA

[4] Vanderbilt Univ, Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Nashville, TN USA

[5] Vet Affairs Tennessee Valley Healthcare Syst, Nashville, TN USA

[6] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA

来源：

DIABETES | 2010年 / 59卷 / 09期

基金：

美国国家卫生研究院;

关键词：

TRANSPLANTATION TOLERANCE INDUCTION; STEM-CELLS; MOUSE MODEL; BETA-CELLS; ENGRAFTMENT; RESPONSES; PATHWAYS; MELLITUS; MUTATION;

D O I：

10.2337/db10-0323

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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) IL2r gamma(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 IL2r gamma(null), Rag1(null), and Ins2(Akita) genes in NOD-Rag1(null) IL2r gamma(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 IL2r gamma(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. Diabetes 59:2265-2270, 2010

引用

页码：2265 / 2270

页数：6

共 25 条

[1]

Parameters for establishing humanized mouse models to study human immunity: Analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rγnull mutation [J].