New generation humanized mice for virus research: comparative aspects and future prospects.
New generation humanized mice for virus research: comparative aspects and future prospects.
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DOI：
10.1016/j.virol.2012.10.007
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发表时间：
2013-01-05
期刊：
影响因子：
3.7
通讯作者：
Akkina R
中科院分区：
文献类型：
--
作者：
Akkina R
使用体内系统，在生理环境中提供人体靶细胞和组织，对人类特异性病毒的研究将大大受益。在这方面，人源化小鼠（hu-Mice）在我们了解病毒发病机制和测试治疗策略方面发挥了重要作用。早期版本的hu- mouse缺乏正常的人类免疫系统，目前正在克服这些限制。新一代小鼠模型能够多系造血，并产生适应性人类免疫反应所需的T细胞、B细胞、巨噬细胞和树突状细胞。现在，任何可以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。目前采用两种主要的人源化小鼠模型：hu-HSC模型是通过移植人造血干细胞（human hematopoietic stem cells， HSC）建立的，而BLT小鼠模型是通过移植人胎肝、胸腺和HSC建立的。许多人类特异性病毒，如HIV-1、登革热、EBV和HCV，正在这些系统中进行深入研究。这两种模型都允许通过粘膜途径感染HIV-1等病毒，从而允许进行传播预防研究。在两种模型中均可见细胞和体液免疫反应。虽然存在有效的抗原特异性IgM产生，但由于免疫球蛋白类转换效率低下，IgG反应不是最佳的。随着T细胞在自体人胸腺中成熟，BLT小鼠允许人类HLA限制性T细胞反应，与hu-HSC小鼠相反。然而，这两种模型的免疫反应强度需要进一步提高，才能达到人类的水平。通过移植其他组织（如人类肝脏），进一步扩大了hu-小鼠的使用范围，从而允许对HCV等嗜肝病毒进行免疫发病机制研究。包括抗病毒药物、基因治疗、病毒进化和人类单克隆抗体的产生在内的大量研究已经在这些小鼠中进行，并取得了令人鼓舞的结果。为了进一步完善新的hu-Mouse模型，正在进行的工作集中在产生新的免疫缺陷小鼠品系，转基因人类HLA分子，以加强免疫应答和人类细胞因子和生长因子，以改善人类细胞重建和其稳态维持。
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.
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