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From immunodeficiency to the human immune system: What is the curious evolution of humanized mouse models?
Within the field of medical research, the emergence of humanized mice has provided unprecedented opportunities to explore the mechanisms of human disease. These genetically modified mice harbor functional human genes, cells, tissues, or organs, making them ideal models for understanding unique human physiology and pathology. These mice are widely used in biological and medical research and play a key role in the development of human treatments.
Humanized mouse models can be used to gain insights into human-specific pathologies, which are critical for a deep understanding of the immune system.
Looking back at the history of humanized mice, the athymic mouse (nude mouse) and severe combined immunodeficient mouse (SCID mouse) in the 1980s are important milestones. The findings in these mice paved the way for subsequent research. The earliest athymic mice had an underdeveloped thymus due to a genetic mutation and were therefore unable to produce mature T cells. Although athymic mice are useful in studying immune diseases, they are not suitable as an ideal humanized mouse model because they still retain B cells and natural killer cells (NK cells).
With the advancement of science, researchers transferred SCID mutations into non-obese diabetic mice (NOD) and successfully developed NOD-scid mice. These mice lacked T cells, B cells and NK cells, making the reconstruction of human cells a possible. The next major breakthrough was the introduction of IL-2 receptor (IL2rg) mutations and the further development of NOD-scid-γcnull mice (NSG or NOG). These mice were functionally deficient in multiple interleukin signaling and became potency-deficient mice. A stronger humanized mouse model.
The development of these models allows researchers to observe human immune responses in a more realistic way in an in vivo environment.
Over time, researchers have further optimized these models, especially in knocking out the RAG gene. This ultimately resulted in RAGnull NSG mice, which are devoid of B cells, T cells, or even macrophages and dendritic cells. These mice are among the most immunodeficient mouse models known to date. However, such models still lack the human leukocyte antigen (HLA) of human major histocompatibility antigens, which prevents human T cells from recognizing human antigen-presenting cells after transplantation, thus affecting the normal operation of the immune response.
Researchers introduced HLA I and HLA II transgenes in NSG RAGnull mice, which paves the way for establishing a diverse repertoire of human T cells and corresponding immune responses. Such genetically modified mice are more like hybrids between humans and animals, providing an important experimental platform for studying the human immune system.
Different types of humanized mouse models
Humanized mice can be created by transplanting functional human cells into immune-deficient mice or through genetic engineering techniques. The following is an introduction to several major humanized mouse models:
Hu-PBL-scid model
This model, by injecting human peripheral blood lymphocytes (PBMCs) into immunodeficient mice, has been widely used to study pathologies related to Epstein-Barr virus, HIV infection, and autoimmune diseases, and has provided in-depth insights into factors in psychopathology. The establishment process of this model is relatively simple and can be put into use quickly.
Hu-SRC-scid model
The Hu-SRC-scid model establishes a more mature immune system for studying multi-system development by implanting human CD34+ hematopoietic stem cells in immunodeficient mice. However, this model takes longer to mature and levels of certain immune cells remain low.
BLT model
The BLT model is a highly efficient model containing human hematopoietic stem cells, bone marrow, liver and thymus, demonstrating a complete and functional human immune system. Although this model is excellent at reconstituting human immune cells, it is relatively complicated because it requires surgical implantation.
The development of these models not only enriches the study of human diseases, but is also an integral part of future medical innovation.
Established human disease models
Humanized mouse models have shown great potential in the study of several disease mechanisms, including infectious diseases, cancer, autoimmune diseases, etc. These models allow researchers to explore a variety of relevant factors related to human diseases and their pathogenesis.
Infectious diseases
Researchers have successfully explored a variety of human-specific pathogens such as human immunodeficiency virus (HIV), Ebola virus, and hepatitis virus on these mouse models, greatly advancing the understanding of these diseases.
Cancer
Depending on the type of human cells or tissues used, humanized mouse models can be divided into patient-derived xenograft (PDX) models and cell line-derived xenograft models. These models play an important role in preclinical research on cancer drugs.
Autoimmune diseases
The use of humanized mice has greatly increased the possibility of studying autoimmune diseases, whether it is multiple sclerosis or systemic lupus erythematosus, allowing researchers to gain a deeper understanding of the immune responses behind them.
As humanized mouse models continue to be developed, researchers are making great strides in understanding the complexities of the human immune system and disease. However, the potential limitations and ethical considerations of these models still need to be carefully considered in future research. Whether they can be effectively integrated into our scientific and medical progress is still a question worthy of our consideration.
