Scientists have created a mouse with fully human immunity
"Mice are not people," biologists like to say, emphasising the difficulty of transferring experimental results from rodents to humans. To some extent, the authors of a new study have overcome this problem by creating a modified line of TruHuX (or "truly humanised") mice. These animals have a full human immune system and the same gut microbiome.
Mice, and to a lesser extent rats, are the most important animal models used to study the development of human disease and how to treat it. Small rodents are particularly convenient: they are unpretentious, grow and reproduce quickly, and have biochemical and cellular processes very close to our own. Besides, it is easy to make mice transgenic - to introduce into their genome DNA encoding human proteins. Including pathological ones, i.e. those that cause certain diseases.
Immunity is a bit more complicated. Although rodents in general have an immune system close to ours, there are important differences, because the ancestors of humans and mice evolved independently of each other over tens of millions of years. So now the set of about 1,600 mouse genes responsible for their response to infections and immune pathologies is very different.
How can we study human immunity and diseases in mice? For this purpose, rodents are being humanised, i.e. made "humanised". Such experiments began in the 1980s at the dawn of the HIV epidemic and are still being actively conducted today.
First, they destroy the mice's own immune system, causing immunodeficiency; this "clears" a place for human immune components. Then the animals are injected with human cells - mature lymphocytes from blood, haematopoietic stem cells or some other cells. Such a humanised mouse reproduces only individual components of immunity, is not capable of a full protective response and lives a short time. These models are ill-suited for studying many diseases, creating immunotherapies for real patients, and producing vaccines. An important step forward in the case of "humanising" animals was an article by American scientists in the journal Nature Immunology. Biologists have created a new line of mice, which they called "truly humanised" (TruHuX, from the English truly human).
As a basis they took a mutant line of mice NSG W41, which did not have a full immune system. Human stem cells isolated from umbilical cord blood were injected into their heart (more specifically, the left ventricle). After a few weeks, the mice were exposed to 17b-estradiol (E2), the most active and common form of female sex hormone. It is available in both males and females.
The fact is that in addition to being involved in reproduction and the formation of sex characteristics, this estrogen also acts on the immune system. It stimulates the survival of human stem cells, differentiation of B-lymphocytes, as well as the production of antibodies to viruses and bacteria.
TruHuX (or THX) mice obtained after this treatment have a complete immune system, which is composed of human cells. It includes lymph nodes, germinal centres, thymus epithelial cells, T- and B-lymphocytes, including memory B-cells, and plasma cells that produce highly specific antibodies and autoantibodies.
The authors showed that the modified mice were capable of a strong immune response due to antibodies to proteins from the bacterium Salmonella typhimurium (the causative agent of salmonellosis) as well as the SARS-CoV-2 coronavirus. For this purpose, the animals were inoculated with vaccines that are used in the clinic and administered to humans. By administering a specific toxin (pristan) to other TruHuX mice, systemic lupus erythematosus, a severe autoimmune disease, was induced. In addition, rodents have a "human" gut microbiome, which is important for both immune function and a number of other biological processes.
These findings could take immunity research to a new level, as well as contribute to the development of new effective drugs. Perhaps TruHuX mice and the like will allow us to do away with immunological and microbiological studies on great apes, which is very expensive and causes ethical difficulties.