Scientists develop first fully functional human immune system in mouse model

Researchers at The University of Texas Health Science Center in San Antonio have produced a mouse model that is humanized, complete with a human immune system and a gut microbiome that resembles that of a human being and is able to elicit particular antibody responses. A breakthrough in biomedical research holds new possibilities for modeling diseases and developing immunotherapies.

The multi-year project's goal was to create a humanized mouse with a fully developed and functional human immune system, which would allow it to overcome the limitations of the in vivo human models that are currently available.

Due to their small size, ease of handling, similarity to human biology and immune systems, and ease of genetic modification, mice are frequently used in biological and biomedical research. But many of the more than 1,600 immune response mouse genes do not match their human counterparts, leading to either a deficiency or divergence in the ability of mice to predict human immune responses.

Due to this, it became extremely important to have a "humanized" mouse model that accurately mimics human immune responses.

In the 1980s, the first humanized mice were developed to simulate HIV infection in humans and the immune system's reaction to the virus. Immunodeficient mice were injected with human peripheral lymphocytes, hematopoietic stem cells, or other human cells to produce humanized mice, which have since been produced.

However, both past and present models cannot generate a fully functional human immune system, live only a short time, and develop effective immune responses. This renders them inappropriate for the development of human vaccines, in vivo human immunotherapies, or human disease modeling.

Initially, Casali's group injected human stem cells that they had isolated from umbilical cord blood intracardially (left ventricle) into immunodeficient NSG W41 mutant mice. The most powerful and prevalent form of estrogen in the body, 17b-estradiol (E2), is used to hormonally condition the mice after a few weeks, once the graft has become established.

Previous studies by Casali and colleagues, suggested that estrogen increases human stem cell survival, B lymphocyte differentiation, and the generation of antibodies against bacteria and viruses, served as the impetus for hormone conditioning by estrogen.

The resultant humanized mice are known as TruHuX (for truly human, or THX), and they have a human immune system that is fully developed and functional. This immune system consists of human T and B lymphocytes, memory B lymphocytes, germinal centers, lymph nodes, human epithelial cells in the thymus, and plasma cells that produce highly specific autoantibodies and antibodies that are identical to those found in humans.

Salmonella Typhimurium and SARS-CoV-2 virus Spike S1 RBD induces mature neutralizing antibody responses in THX mice following vaccination with Salmonella flagellin and the Pfizer COVID-19 mRNA vaccine, respectively. Additionally, THX mice are susceptible to developing a full-blown systemic lupus autoimmunity following an injection of pristane, an oil that incites inflammation.

According to Casali, the discovery of the THX mouse provides opportunities for in vivo experiments on humans, the creation of immunotherapeutics like cancer checkpoint inhibitors, the development of human bacterial and viral vaccines, and the modeling of numerous human diseases.

Casali hopes that the use of non-human primates in immunological and microbiological biomedical research may become unnecessary due to the new methodology.

Casali hopes this discovery spurs more research on the topic because there has not been much done in the past regarding the relationship between estrogen and the immune system.

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.”

Paolo Casali, Distinguished Research Professor, The University of Texas Health Science Center in San Antonio

Using the THX model, the Casali lab is currently studying human memory B lymphocytes, their reliance on nuclear receptor RORα for generation, and the processes that result in RORα expression and dysregulation, as well as the in vivo human immune response to SARS-CoV-2 (COVID-19) at the systemic and local levels.

It investigates the epigenetic mechanisms and factors that mediate the generation of human plasma cells, which are the cell factories responsible for producing thousands of antibodies per second against bacteria, viruses, or cancer cells.