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Scientists create first mouse model with complete, functional human immune system


Contacts:

Eileen Teves, 210-450-7239, tevese@uthscsa.edu

Steven Lee, 210-450-3823, lees22@uthscsa.edu

Content by Claire Kowalick

SAN ANTONIO, July 8, 2024 — 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 (UT Health 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 scientists were led by Paolo Casali, MD, University of Texas Ashbel Smith Professor and Distinguished Research Professor, Department of Microbiology, Immunology and Molecular Genetics in the Joe R. and Teresa Lozano Long School of Medicine. Casali has nearly five decades of biomedical research experience in immunology and microbiology and is a leading researcher in molecular genetics and epigenetics of the antibody response. He was a professor of immunology and director of the division of molecular immunology at Weill Cornell Medical College, New York, NY, and the founding director of the Institute for Immunology at University of California, Irvine, CA.

“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.

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.

Casali’s team began with injecting immunodeficient NSG W41 mutant mice intracardiacally (left ventricle) with human stem cells they purified from human umbilical cord blood. After a few weeks, once the graft has been established, the mice are hormonally conditioned with 17beta-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.

THX mice mount mature neutralizing antibody responses to Salmonella Typhimurium and SARS-CoV-2 virus Spike S1 RBD after vaccination with Salmonella flagellin and the Pfizer COVID-19 mRNA vaccine, respectively. THX mice are also amenable to developing full-fledged systemic lupus autoimmunity after an injection of pristane, an oil that triggers an inflammatory response.

Casali said the THX mouse discovery opens the possibilities for human in vivo experimentation, for development of immunotherapeutics such as cancer checkpoint inhibitors, development of human bacterial and viral vaccines, as well as the modeling of many human diseases. He also hopes the new approach could make obsolete the use of non-human primates for select immunological and microbiological biomedical investigations.  As prior research on the effect of estrogen and the immune system is sparse, Casali hopes this discovery prompts further research into the topic.

Additional link: Scientists create first mouse model with complete, functional human immune system – UT Health San Antonio (uthscsa.edu)


The University of Texas Health Science Center at San Antonio (UT Health San Antonio) is one of the country’s leading health science universities and is designated as a Hispanic-Serving Institution by the U.S. Department of Education. With missions of teaching, research, patient care and community engagement, its schools of medicine, nursing, dentistry, health professions, graduate biomedical sciences and public health have graduated more than 43,886 alumni who are leading change, advancing their fields and renewing hope for patients and their families throughout South Texas and the world. To learn about the many ways “We make lives better®,” visit UTHealthSA.org.

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