In a breakthrough for biomedical research, a team from The University of Texas Health Science Center at San Antonio has engineered the world’s first mouse model with a fully functional and human-like human immune system. Dubbed TruHuX, meaning truly human, or THX, the new model will revolutionize the development of immunotherapies and new disease modeling.
The research team, led by Ashbel Smith Professor and Distinguished Research Professor Paolo Casali, MD, at the University of Texas, has done what many considered impossible. Casali brings nearly five decades of experience in the field of immunology and microbiology and called this development very important. “By critically leveraging estrogen activity to support human stem cell and human immune cell differentiation and antibody responses, THX mice provide a platform for human immune system studies, development of human vaccines, and testing of therapeutics,” he said.
A multi-year project described in an August 2024 issue of the journal Nature Immunology aimed to improve upon the deficiencies of current in vivo models of humans. While very useful, traditional mouse models have gross discrepancies compared with human immune responses. One of the critical tasks at that time was to generate a humanized mouse model that would really mimic human immune responses.
The first humanized mice were generated back in the 1980s, with the idea of investigating human HIV infection and immune responses. However, these models succumbed very early, as they did not have a fully reconstructed human immune system. Thus, study, together with vaccine development, remained a tough task. By contrast, the THX mice have a human immune system reconstituted to the point of having an integrated and functional human immune system that includes lymph nodes, germinal centers, thymus human epithelial cells, human T and B lymphocytes, memory B lymphocytes, and plasma cells producing highly specific antibodies and autoantibodies identical to those of humans.
Here, we engrafted purified human stem cells from umbilical cord blood into immunodeficient NSG W41 mutant mice. After graft establishment in these mice, hormonal conditioning was done with 17b-estradiol, the most potent/predominant circulating estrogen in human beings. This was according to previous findings that estrogen improved the survival of human stems and at the same time stimulated B lymphocyte differentiation and antibody production.
The THX mice were shown to mount mature neutralizing antibody responses against both Salmonella Typhimurium and the SARS-CoV-2 virus Spike S1 RBD upon vaccination with Salmonella flagellin and the Pfizer COVID-19 mRNA vaccine, respectively. Furthermore, such mice are permissive for the progression of full-fledged systemic lupus autoimmunity following an injection of pristane, an oil that induces inflammation.
Casali underlined the broader implications of this observation, citing the potential opening of various new avenues for human in vivo experimentation related to the development of such immunotherapeutics as cancer checkpoint inhibitors, bacterial and viral vaccines for humans, and modeling various human diseases. He finally outlined hopes that this new paradigm could eventually eliminate the use of non-human primates in immunological and microbiological biomedical research.
The research team investigates further the in vivo human immune response against SARS-CoV-2 on both systems and local levels, exploring epigenetic factors and mechanisms mediating the generation of human plasma cells. These cells are crucial for producing antibodies to bacteria, viruses, or cancer cells.
TruHuX mice represent a bridge across human biology and experimental investigation in this changing scene of biomedical innovation, pioneering new horizons in the quest for healthier futures.
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