Scientists at The University of Texas Health Science Center at San Antonio have created a humanized mouse model with a human immune system and gut microbiome that can produce specific antibodies. Led by Paolo Casali, an expert in immunology and microbiology with nearly five decades of experience, this breakthrough promises new insights into immunotherapy and disease modeling.
The multi-year project, featured in the August 2024 issue of Nature Immunology, aimed to create a humanized mouse with a fully functional human immune system, overcoming the limitations of existing models. Mice are popular in research due to their similarity to humans and ease of genetic modification.
However, differences in immune response genes have limited their effectiveness. Previous humanized mice, created since the 1980s, have not fully replicated human immune responses, making them inadequate for immunotherapy and vaccine development. This new model addresses those issues.
Casali’s team injected immunodeficient NSG W41 mutant mice with human stem cells from umbilical cord blood. After a few weeks, the mice were treated with 17b-estradiol (E2) to boost human stem cell survival and antibody production.
The resulting humanized mice, TruHuX, developed a fully functional human immune system, including lymph nodes, thymus, T and B lymphocytes, and memory B cells producing human-like antibodies.
THX mice produce strong antibody responses to Salmonella Typhimurium and SARS-CoV-2 after vaccination. They can also develop systemic lupus after an injection of pristane. Casali believes the THX mice could revolutionize human in vivo experimentation, immunotherapy development, vaccine creation, and disease modeling. He hopes this model will reduce the need for non-human primates in research and encourage further study on the effects of estrogen on the immune system.
Casali said, “By using estrogen to support human stem cell and immune cell differentiation, THX mice offer a platform for studying the human immune system, developing vaccines, and testing therapies.”
The Casali lab uses the THX model to investigate the human immune response to COVID-19, the role of memory B lymphocytes, the dependence on the nuclear receptor RORα, and the epigenetic factors involved in generating human plasma cells that produce antibodies.
Journal reference:
- Chupp, D.P., Rivera, C.E., Zhou, Y. et al. A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses. Nature Immunology. DOI: 10.1038/s41590-024-01880-3.