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

Scientists at The University of Texas Health Science Center at San Antonio have made a groundbreaking achievement in biomedical research by creating a mouse model that possesses a complete and functional human immune system along with a human-like gut microbiome. This development is expected to provide valuable insights into the development of immunotherapy and disease modeling.

Led by renowned researcher Paolo Casali, MD, the team aimed to overcome limitations posed by existing in vivo human models by creating a humanized mouse with an authentic and fully functional human immune system. Mice are commonly used in biological and biomedical research due to their manageable size, shared immune elements with humans, and ease of genetic modification. However, their immune response diverges from the human equivalent, rendering them inadequate predictors of human immune responses. Creating a mouse model that faithfully replicates human immune responses has been a top priority.

The first humanized mice came into existence in the 1980s for the purpose of studying human immune response to HIV infection. Although humanized mice have been developed by injecting immunodeficient mice with human cells such as peripheral lymphocytes or hematopoietic stem cells, previous models have not been capable of fully developing functional human immune systems, leading to limitations in various areas such as human immunotherapy research, disease modeling, and vaccine development.

Casali's team approached the challenge by injecting immunodeficient NSG WW41 mutant mice with human stem cells obtained from purified umbilical cord blood. After the graft was successfully established, the mice underwent hormonal conditioning with 17b-estradiol (E2), a potent form of estrogen. This conditioning was based on previous research suggesting that estrogen enhances the survival of human stem cells, boosts B lymphocyte differentiation, and encourages the production of antibodies against viruses and bacteria.

The resulting humanized mice, known as TruHuX (THX), possess a fully developed and functional human immune system, complete with important components like lymph nodes, germinal centers, thymus human epithelial cells, human T and B lymphocytes, memory B lymphocytes, and plasma cells capable of producing highly specific antibodies and autoantibodies akin to those found in humans. THX mice exhibited mature neutralizing antibody responses to Salmonella Typhimurium and the Spike S1 RBD of the SARS-CoV-2 virus after being vaccinated. They also demonstrated susceptibility to developing systemic lupus autoimmunity when injected with pristane, an oil that triggers an inflammatory response.

CasalmpleexasT expressed optimism that the THX mouse model will revolutionize human in vivo experimentation, immunotherapy development, vaccine testing, and disease modeling. If successful, it could potentially render the use of non-human primates unnecessary in immunological and biomedical research. Furthermore, the discovery of the role estrogen plays in supporting human stem cell differentiation and immune cell responses could unlock even more avenues for future research.

Casali and his team are currently utilizing the THX model to investigate the human immune response to COVID-19 at both systemic and local levels. They are also studying human memory B lymphocytes, exploring the relevance of the nuclear receptor RORα in generating these cells, and delving into the factors and mechanisms that contribute to the generation of human plasma cells, which are responsible for producing thousands of antibodies per second in response to bacteria, viruses, or cancer cells.