For the first time, scientists have successfully created a type of mouse with a 100% functional human immune system and human-like gut microbiome. This 'humanized' mouse takes the guesswork out of medical research and has the potential to revolutionize how we test new drugs and unlock disease mechanisms.
Researchers at The University of Texas Health Science Center at San Antonio have succeeded where many before them have failed, in engineering a type of mouse that has an immune response identical to humans. While mice are commonplace in research and considered one of the best animals to work with, they're far from a perfect human substitute. A major challenge is the many genes in mice that diverge from human equivalents, so their immune system responds very differently to ours.
This new mouse type – known as TruHuX (aka truly human) or THX – stands to make this research barrier a thing of the past. With its fully functional human immune system, the mouse ultimately responds to treatment as any of us would.
“THX mice provide a platform for human immune system studies, development of human vaccines and testing of therapeutics,” said Paolo Casali, MD, who led this groundbreaking study.
So what does this mean for everyone outside of medical research? It has the potential to greatly accelerate drug and immunotherapy development, slashing 'trial and error' timelines, and allows scientists to take treatments into human trials with more confidence surrounding efficacy and safety. Casali also believes the THX mice could do away with the current immunological and microbiological testing on non-human primates.
The mice also open the door to new cancer immunotherapeutics, bacterial and viral vaccine development, and disease modeling.
At some point in the future, it's likely that technology will facilitate the creation of complex artificial models to replace animals in medical testing, but until then, it unfortunately remains a crucial part of drug development and disease research. And scientists have been working to perfect the humanized mouse for decades.
The first, engineered in the 1980s to model human HIV infection and the body's response to it, continues to be an important part of research. Until now, scientists developed this model by injecting immunodeficient mice with human peripheral lymphocytes, immature hematopoietic stem cells or other human cells. But these mice tend to be short-lived, develop a host of health problems as a result of their 'humanizing,' and pose the same issue as other mouse models in that their immune system mounts a very different response to that of a human.
Casali's team also started with immunodeficient mice (NSG W41 mutants), injecting human stem cells purified from umbilical cord blood through the animal's left ventricle. After a period of weeks to allow this graft to settle, the mice were hormonally conditioned with 17b-estradiol (E2) – estrogen. Previous research by the team had found that this potent estrogen form could boost stem-cell survival and lymphocyte differentiation, as well as activate antibodies in response to viruses and bacteria.
Ultimately, THX is a 'super-humanized' mouse, with a complete human immune system – lymph nodes, germinal centers, thymus human epithelial cells, human T and B lymphocytes, memory B lymphocytes and plasma cells – and one that could mount a response identical to ours.
The team is now using the THX mice to better understand the human immune response to SARS-CoV-2, as well as looking into epigenetic factors involved in human plasma cell activity and their antibody response, which has the potential to unlock new viral and cancer therapies.
The study was published in the journal Nature Immunology.
Source: The University of Texas Health Science Center at San Antonio
