Human immune system development and survival of non-obese diabetic (NOD)-scid IL2rγnull (NSG) mice engrafted with human thymus and autologous haematopoietic stem cells
Human immune system development and survival of non-obese diabetic (NOD)-scid IL2rγnull (NSG) mice engrafted with human thymus and autologous haematopoietic stem cells
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DOI：
10.1111/cei.12180
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发表时间：
2013-12-01
影响因子：
4.6
通讯作者：
Brehm, M. A.
中科院分区：
文献类型：
--
作者：
Covassin, L.;Jangalwe, S.;Brehm, M. A.
携带IL 2 rg基因靶向突变并植入人免疫系统的免疫缺陷小鼠是研究人造血、免疫、感染性疾病和移植生物学的有效工具。最稳健的人免疫模型是通过将人胎胸腺和肝脏组织植入受辐射者体内，然后静脉注射自体胎肝造血干细胞[通常称为BLT（骨髓、肝脏、胸腺）模型]。为了评估非肥胖糖尿病（NOD）-scid IL 2 r（null）（NSG）-BLT模型，我们评估了各种移植参数以及这些参数如何影响NSG-BLT小鼠的寿命。我们观察到，辐射和肾包膜下植入胸腺/肝脏片段是产生人类免疫系统的最佳方法。然而，4个月后，大量NSG-BLT小鼠发展出致命的移植物抗宿主病（GVHD）样综合征，其与人T细胞的活化和人免疫球蛋白（IG）水平的增加相关。在缺乏鼠主要组织相容性复合体（MHC）I或II类的NSG小鼠中，GVHD的发生没有延迟，并且与人类调节性T细胞的丢失或小鼠胸腺内细胞（小鼠CD 45（+））的缺乏无关。我们的研究结果表明，NSG-BLT小鼠发展强大的人类免疫系统，但这些小鼠的实验窗口可能受到GVHD样病理变化的发展的限制。
Immunodeficient mice bearing targeted mutations in the IL2rg gene and engrafted with human immune systems are effective tools for the study of human haematopoiesis, immunity, infectious disease and transplantation biology. The most robust human immune model is generated by implantation of human fetal thymic and liver tissues in irradiated recipients followed by intravenous injection of autologous fetal liver haematopoietic stem cells [often referred to as the BLT (bone marrow, liver, thymus) model]. To evaluate the non-obese diabetic (NOD)-scid IL2r(null) (NSG)-BLT model, we have assessed various engraftment parameters and how these parameters influence the longevity of NSG-BLT mice. We observed that irradiation and subrenal capsule implantation of thymus/liver fragments was optimal for generating human immune systems. However, after 4 months, a high number of NSG-BLT mice develop a fatal graft-versus-host disease (GVHD)-like syndrome, which correlates with the activation of human T cells and increased levels of human immunoglobulin (Ig). Onset of GVHD was not delayed in NSG mice lacking murine major histocompatibility complex (MHC) classes I or II and was not associated with a loss of human regulatory T cells or absence of intrathymic cells of mouse origin (mouse CD45(+)). Our findings demonstrate that NSG-BLT mice develop robust human immune systems, but that the experimental window for these mice may be limited by the development of GVHD-like pathological changes.