Important Takeaways:

• A breakthrough for biomedical research promises new insight into immunotherapy development and disease modeling. Scientists at The University of Texas Health Science Center at San Antonio have created a humanized mouse model with a human immune system and a human-like gut microbiome that is capable of mounting specific antibody responses.
• The aim of the multi-year project, which appears in the August 2024 issue of Nature Immunology, was to overcome limitations of currently available in vivo human models by creating a humanized mouse with a fully developed and functional human immune system.
• Mice are widely used in biological and biomedical research because they are small, easy to handle, share many immune elements and biological properties with humans and are easily genetically modified. Many of the more than 1,600 immune response mouse genes, however, are incongruent with their human equivalents, resulting in divergencies or deficiencies of mice as predictors of human immune responses. This made availability of a “humanized” mouse model that faithfully reproduces human immune responses a high priority.
• The first humanized mice were created in the 1980s to model human HIV infection and the human immune response to HIV.
• Casali’s team began with injecting immunodeficient NSG W41 mutant mice intracardiacally (left ventricle) with human stem cells they purified from umbilical cord blood. After a few weeks, once the graft has been established, the mice are hormonally conditioned with 17b-estradiol (E2), the most potent and abundant form of estrogen in the body. Hormonal conditioning by estrogen was prompted by previous research by Casali and others suggesting that estrogen boosts the survival of human stem cells, boosts B lymphocyte differentiation and production of antibodies to viruses and bacteria.
• The resulting humanized mice, called TruHuX (for truly human, or THX), possess a fully developed and fully functional human immune system, including lymph nodes, germinal centers, thymus human epithelial cells, human T and B lymphocytes, memory B lymphocytes, and plasma cells making highly specific antibody and autoantibodies identical to those of humans.
• “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,” Casali said.

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