The development and improvement of immunodeficient mice and humanized immune system mouse models

Abstract

Animal models play an indispensable role in the study of human diseases. However, animal models of different diseases do not fully mimic the complex internal environment of humans. 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. Here, we summarize the developments in immunodeficient mice, from the initial nude mice lacking T lymphocytes to NOD/SCID rgnull mice lacking T, B, and NK cell populations. 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. The different methods for their development involve varying levels of complexity and humanization. Humanized mice are widely used in the study of various diseases to provide a transitional stage for clinical research. 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. 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.

Patient-derived tumor models: a suitable tool for preclinical studies on esophageal cancer

“…Nude mice are the earliest immunodeficient mouse strains. Mice with allele mutations in the foxn1 gene on chromosome 11 exhibit a hairless phenotype, congenital athymia, and the inability to produce T lymphocytes such that their range of immune responses involving lymphocytes is restricted [8]. However, in nude mice, T lymphocytes leak to a certain extent during growth [9], and B lymphocytes and NK cells remain active and mediate a series of immune responses.…”

Zebrafish: A Relevant Genetic Model for Human Primary Immunodeficiency (PID) Disorders?

“…Finally, xenotransplantation studies typically employ compromised temperatures and other conditions to enable human cells to be propagated in zebrafish [ 120 ]. For some studies, mouse models may be superior, although they too have limitations [ 142 ].…”

“…Regeneration studies can also consider other immune populations, including for example, adaptive immune cells, dendritic cells, mast cells and M1 versus M2 macrophages [ 19 , 106 ]. Future cancer studies can further study the role of angiogenesis [ 122 ] and better mimic the human tumor microenvironment [ 129 ], including creating humanized models as achieved in mice [ 142 ]. Finally, so-called cancer ‘avatars’ have application in patient-specific ‘precision’ cancer therapy pipelines, with the potential to directly predict patient outcomes and thus influence individual patient care [ 143 , 144 ].…”

Animal models of bone metastatic prostate cancer

“…However, subspecies of R3327 only metastasized to the lymph nodes and lungs and did not form bone metastasis, limiting its usefulness in research of bone metastatic disease [ 30 ]. Dogs were also found to spontaneously acquire prostate cancer, and studies found that prostate cancer in dogs were not only rare, but lacked the membrane androgen receptor (AR) [ 31 32 ]. As a result, prostate hyperplasia seen in dogs always occur independently of ARs, which limits its application to human prostate disease research [ 33 34 ].…”

“…To conduct more in-depth studies on the efficacy of immunotherapy in bone metastatic prostate cancer, animal models utilizing human prostate cancer cells that mimic the metastatic cascade and form osteoblastic bone lesions while maintaining immune capacity are needed. Researches regarding immunodeficient mice with humanized immune systems are under development and may help to alleviate the hardships of studying immunotherapy with animal models [ 32 ].…”