The University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, United States.
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, United States.
J Immunol Methods. 2014 Aug;410:3-17. doi: 10.1016/j.jim.2014.02.011. Epub 2014 Mar 4.
The study of human-specific infectious agents has been hindered by the lack of optimal small animal models. More recently development of novel strains of immunodeficient mice has begun to provide the opportunity to utilize small animal models for the study of many human-specific infectious agents. The introduction of a targeted mutation in the IL2 receptor common gamma chain gene (IL2rg(null)) in mice already deficient in T and B cells led to a breakthrough in the ability to engraft hematopoietic stem cells, as well as functional human lymphoid cells and tissues, effectively creating human immune systems in immunodeficient mice. These humanized mice are becoming increasingly important as pre-clinical models for the study of human immunodeficiency virus-1 (HIV-1) and other human-specific infectious agents. However, there remain a number of opportunities to further improve humanized mouse models for the study of human-specific infectious agents. This is being done by the implementation of innovative technologies, which collectively will accelerate the development of new models of genetically modified mice, including; i) modifications of the host to reduce innate immunity, which impedes human cell engraftment; ii) genetic modification to provide human-specific growth factors and cytokines required for optimal human cell growth and function; iii) and new cell and tissue engraftment protocols. The development of "next generation" humanized mouse models continues to provide exciting opportunities for the establishment of robust small animal models to study the pathogenesis of human-specific infectious agents, as well as for testing the efficacy of therapeutic agents and experimental vaccines.
人类特异性传染因子的研究一直受到缺乏理想的小动物模型的阻碍。最近，免疫缺陷型小鼠新型品系的发展开始为许多人类特异性传染因子的研究提供了利用小动物模型的机会。在已经缺乏 T 细胞和 B 细胞的小鼠中引入白细胞介素 2 受体共同γ链基因（IL2rg(null)）的靶向突变，导致了能够植入造血干细胞以及功能性人类淋巴样细胞和组织的突破，有效地在免疫缺陷型小鼠中创建了人类免疫系统。这些人源化小鼠作为人类免疫缺陷病毒-1（HIV-1）和其他人类特异性传染因子的临床前模型变得越来越重要。然而，仍然有许多机会可以进一步改进用于研究人类特异性传染因子的人源化小鼠模型。这是通过实施创新技术来实现的，这些技术将共同加速新型基因修饰小鼠模型的开发，包括：i）宿主的修饰以减少阻碍人类细胞植入的固有免疫；ii）基因修饰以提供最佳人类细胞生长和功能所需的人类特异性生长因子和细胞因子；iii）以及新的细胞和组织植入方案。“下一代”人源化小鼠模型的发展继续为建立强大的小动物模型以研究人类特异性传染因子的发病机制以及测试治疗剂和实验疫苗的疗效提供了令人兴奋的机会。
