![]() The main immunoglobulin in these mice is IgM ( 8), with little or no IgA. Owing to an allele mutation on chromosome 11, a resultant defect in the Foxn1 gene prevents normal thymus development ( 7), thereby leading to a mature T lymphocyte deficiency. Nude mice are the earliest immunodeficient mouse model, first reported by Flanagan in 1966 ( 1). The characteristics of different immunodeficient mice are summarized in Figure 1. To improve this situation, the fourth stage of immunodeficient mice, NOD/SCID rg null mice, was developed by knocking out the IL-2 receptor gamma chain (IL-2 rg) these knock-out mice had a higher rate of human-cell implantation without leakage or spontaneous thymomas, and are currently the gold standard immunodeficient mouse model ( 6). Therefore, their application as a humanized animal model has remained limited ( 5). However, these mice exhibit a high frequency of spontaneous thymic lymphoma and short life cycles, as well as partial NK cell activity. The SCID mutation was then introduced into non-obese diabetic (NOD) mice with NK cell defects to obtain NOD/SCID mice ( 5), forming the third stage of immunodeficient mice. SCID mice are deficient in T and B lymphocytes, but retain natural killer (NK) cells and show “leakage” ( 4). The second stage included mice with severe combined immunodeficiency (SCID), carrying a mutation of the Prkdc gene ( 2, 3). However, the application of nude mice in many diseases remains limited because of their low relative degree of immunodeficiency. The first stage included nude mice that are simply deficient in T lymphocytes owing to abnormal thymus development ( 1). The development of immunodeficient mice occurred in four main stages. Overall, there are many opportunities and challenges in the development of humanized immune system mouse models which can provide novel strategies for understanding the mechanisms and treatments of human disease. However, several challenges persist, including improving the efficiency of reconstructing the human B cell immune response, extending lifespan, improving the survival rate of mice to extend the observation period, and improving the development of standardized commercialized models and as well as their use. Humanized mice are widely used in the study of various diseases to provide a transitional stage for clinical research. The different methods for their development involve varying levels of complexity and humanization. We describe existing humanized immune system mouse models based on immunodeficient mice in which human cells or tissues have been transplanted to establish a human immune system, including humanized-peripheral blood mononuclear cells (Hu-PBMCs), humanized hematopoietic stem cells (Hu-HSCs), and humanized bone marrow, liver, thymus (Hu-BLT) mouse models. Here, we summarize the developments in immunodeficient mice, from the initial nude mice lacking T lymphocytes to NOD/SCID rg null mice lacking T, B, and NK cell populations. Immunodeficient mice are deficient in certain genes and do not express these or show reduced expression in some of their cells, facilitating the establishment of humanized mice and simulation of the human environment in vivo. However, animal models of different diseases do not fully mimic the complex internal environment of humans. Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, ChinaĪnimal models play an indispensable role in the study of human diseases.Jiaxuan Chen † Shuzhen Liao † Zengzhi Xiao Quanren Pan Xi Wang Kangyuan Shen Shuting Wang Lawei Yang Fengbiao Guo Hua-feng Liu * Qingjun Pan *
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