Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Virology. 2013 Jan 5;435(1):14-28. doi: 10.1016/j.virol.2012.10.007.
Work with human specific viruses will greatly benefit from the use of an in vivo system that provides human target cells and tissues in a physiological setting. In this regard humanized mice (hu-Mice) have played an important role in our understanding of viral pathogenesis and testing of therapeutic strategies. Limitations with earlier versions of hu-Mice that lacked a functioning human immune system are currently being overcome. The new generation hu-Mouse models are capable of multilineage human hematopoiesis and generate T cells, B cells, macrophages and dendritic cells required for an adaptive human immune response. Now any human specific pathogen that can infect humanized mice can be studied in the context of ongoing infection and immune responses. Two leading humanized mouse models are currently employed: the hu-HSC model is created by transplantation of human hematopoietic stem cells (HSC), whereas the BLT mouse model is prepared by transplantation of human fetal liver, thymus and HSC. A number of human specific viruses such as HIV-1, dengue, EBV and HCV are being studied intensively in these systems. Both models permit infection by mucosal routes with viruses such as HIV-1 thus allowing transmission prevention studies. Cellular and humoral immune responses are seen in both the models. While there is efficient antigen specific IgM production, IgG responses are suboptimal due to inefficient immunoglobulin class switching. With the maturation of T cells occurring in the autologous human thymus, BLT mice permit human HLA restricted T cell responses in contrast to hu-HSC mice. However, the strength of the immune responses needs further improvement in both models to reach the levels seen in humans. The scope of hu-Mice use is further broadened by transplantation of additional tissues like human liver thus permitting immunopathogenesis studies on hepatotropic viruses such as HCV. Numerous studies that encompass antivirals, gene therapy, viral evolution, and the generation of human monoclonal antibodies have been conducted with promising results in these mice. For further improvement of the new hu-Mouse models, ongoing work is focused on generating new strains of immunodeficient mice transgenic for human HLA molecules to strengthen immune responses and human cytokines and growth factors to improve human cell reconstitution and their homeostatic maintenance.
与人类特异性病毒合作将极大地受益于使用提供生理环境下人类靶细胞和组织的体内系统。在这方面，人源化小鼠（hu-Mice）在我们对病毒发病机制的理解和治疗策略的测试中发挥了重要作用。早期缺乏功能正常的人类免疫系统的 hu-Mice 的局限性目前正在得到克服。新一代 hu-Mouse 模型能够进行多谱系人类造血，并产生 T 细胞、B 细胞、巨噬细胞和树突状细胞，这些细胞是适应性人类免疫反应所必需的。现在，任何能够感染人源化小鼠的人类特异性病原体都可以在持续感染和免疫反应的背景下进行研究。目前使用两种主要的人源化小鼠模型：hu-HSC 模型是通过移植人类造血干细胞（HSC）创建的，而 BLT 小鼠模型是通过移植人类胎肝、胸腺和 HSC 制备的。目前正在这些系统中对许多人类特异性病毒（如 HIV-1、登革热病毒、EBV 和 HCV）进行深入研究。这两种模型都允许通过黏膜途径感染 HIV-1 等病毒，从而允许进行传播预防研究。在这两种模型中都可以观察到细胞和体液免疫反应。虽然有有效的抗原特异性 IgM 产生，但由于免疫球蛋白类别转换效率低下，IgG 反应不理想。随着 T 细胞在自体人类胸腺中成熟，BLT 小鼠允许 HLA 限制的人类 T 细胞反应，而 hu-HSC 小鼠则不允许。然而，为了达到人类水平，两种模型中的免疫反应强度都需要进一步提高。通过移植其他组织（如人类肝脏），hu-Mice 的使用范围进一步扩大，从而可以对丙型肝炎病毒等嗜肝病毒进行免疫发病机制研究。在这些小鼠中进行了许多涵盖抗病毒药物、基因治疗、病毒进化和生成人类单克隆抗体的研究，取得了有希望的结果。为了进一步改进新的 hu-Mouse 模型，正在进行的工作集中在生成新的免疫缺陷小鼠品系，这些小鼠转基因表达人类 HLA 分子以增强免疫反应，以及人类细胞因子和生长因子以改善人类细胞重建及其稳态维持。
