Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Clin Exp Immunol. 2013 Dec;174(3):372-88. doi: 10.1111/cei.12180.
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 IL2rγ(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.
携带 IL2rg 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类造血、免疫、传染病和移植生物学的有效工具。最强大的人类免疫模型是通过将人胎胸腺和肝脏组织植入辐照受者中，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]产生的。为了评估非肥胖型糖尿病（NOD）-scid IL2rγ（null）（NSG）-BLT 模型，我们评估了各种植入参数以及这些参数如何影响 NSG-BLT 小鼠的寿命。我们观察到，辐照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选择。然而，4 个月后，大量 NSG-BLT 小鼠会发展出致命的移植物抗宿主病（GVHD）样综合征，这与人类 T 细胞的激活和人类免疫球蛋白（Ig）水平的升高有关。缺乏鼠主要组织相容性复合物（MHC）I 类或 II 类的 NSG 小鼠中 GVHD 的发作不会延迟，并且与人类调节性 T 细胞的丧失或胸腺内鼠源细胞（鼠 CD45（+））的不存在无关。我们的研究结果表明，NSG-BLT 小鼠可产生强大的人类免疫系统，但这些小鼠的实验窗口可能因 GVHD 样病理变化的发展而受到限制。
