Introduction
Animal models have been a common way to understand and progress research in the biomedical field for several decades, with the common mouse being one of the most widely used. There is a long history of mice being “humanized” to better understand a variety of topics associated with human health, particularly disease response. Earlier this year, a research team was able to create a mouse line with a fully functional human immune system. This article will explore how the mouse with the human immune system came to be and how it can be utilized to advance immunology research.
Humanized Mice
Mouse models are commonly used in biomedical research for a variety of reasons, such as low cost of maintenance, ease of care, and shorter life cycles. However, mice models have not always been reliable in predicting human immune response. To mitigate this, mice were modified in such a way as to express immune cells of the human immune system. This process requires first developing mice who lack their own immune system and then inducing the production of human immune cells, which is typically achieved by engrafting human immune tissues or hematopoietic stem cells. Hematopoietic stem cells (HSCs) are the cells in the body that form both red blood cells and white blood cells (aka immune cells). The introduction of human genes into the mouse genome can also be used as a method to produce humanized mice. [1, 2]
Despite all this, almost all past and current humanized mice face a variety of issues, such as short lifespans, less than adequate immune response, and being unable to develop a fully functional human immune system. [3]
How a Fully Functional Immune System Was Achieved
A research team from the University of Texas led by Paolo Casali, MD, was able to generate the truly human (aka TruHuX or THX) mouse line. To accomplish this, newborn mice from the NSG W41 mutant mouse line (a line that is immunodeficient) had HSCs from human umbilical cord blood injected into the left ventricle of the heart. This HSC injection was further supplemented by hormone conditioning by 17b-estradiol (E2), an abundant and powerful type of estrogen that had been found to aid in stem cell survival, B cell differentiation, and antibody production. [3,4]
THX mice possess all functional parts of a human immune system, from human B and T cells to human lymph nodes and thymus and everything in between. These mice were also found to be able to develop fully mature antibody responses to both Salmonella Typhimurium and the spike protein associated with the SARS-CoV-2 virus spike protein after vaccinations. [3,4]
Current and Potential Applications in Research
Humanized mice have historically been used to study how the human immune system would respond to disease. For example, the first humanized mouse was developed in the 1980s as a means to study the human immune response to HIV. Even today, humanized mice are still used to study a variety of infectious diseases and associated immune responses. In addition to this, humanized mice can also be used to study tumors and cancer, genetic conditions, nervous system development, and the gut microbiome and associated conditions. The THX mouse line further expands the reach of research in these areas due to it possessing a fully functional human immune system. This would allow for a more solid understanding of human disease and potential therapeutics before clinical trials occur in humans. [1,2,3,4]
References:
Walsh, N. C., Kenney, L. L., Jangalwe, S., Aryee, K.-E., Greiner, D. L., Brehm, M. A., & Shultz, L. D. (2017, January 24). Humanized mouse models of clinical disease. PubMed Central. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5280554/
MacNeil, D. (2022, August 31). Brush up: Humanized mice: More than the sum of their parts. The Scientist Magazine. https://www.the-scientist.com/humanized-mice-more-than-the-sum-of-their-parts-70439
Lee, S. (2024, July 25). Scientists create first mouse model with complete, functional human immune system. UT Health San Antonio. https://news.uthscsa.edu/scientists-create-first-mouse-model-with-complete-functional-human-immune-system/
Chupp, D. P., Rivera, C. E., Zhou, Y., Xu, Y., Ramsey, P. S., Xu, Z., Zan, H., & Casali, P. (2024, June 25). A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses. Nature News. https://www.nature.com/articles/s41590-024-01880-3 Assessed and Endorsed by the MedReport Medical Review Board