"Standing on the shoulders of mice" to see "human immunity"?

Although mouse models have provided us with a wealth of information about the modern immune system, they have significant limitations regarding genetic heterogeneity or microbial influence, and are less predictive as models of human disease or vaccination outcomes evaluation. The rapid rise of human research, driven by technological and conceptual advances, promises to fill these gaps and provides direct information on human disease and vaccination responses.

On August 9, 2022, Mark M. Davis and Kwat Medetgul-Ernar from Stanford University School of Medicine published an article titled "Standing on the shoulders of mice" in the journal Immunity, where they proposed to pay attention to mice Anatomical and genetic differences with human immunology, focusing on direct research on human immunity.

Is the mouse model outdated?

Mouse models of cancer have been the focus of immunologists since Snell developed the inbred mouse strain in the late 1940s, and researchers interested in autoimmunity and infectious diseases soon joined. By the 1980s, the advent of recombinant DNA methods and transgenic technologies, followed by gene ablation, etc., made mouse disease models a major avenue for understanding the role of the immune system in nearly all diseases thought to be relevant.

However, it has been known for many years that many mouse transformation models fail when it comes to autoimmunity, tumor immunity, etc. Regarding how to handle mouse models, Sanofi's chief scientific officer and director of global R&D, Frank Nestle, said, "the translational drug discovery paradigm is shifting from mouse-first to people-first."

Is the mouse model still worth learning from?

Many genes and cell types crucial to human function are shared by humans and mice, including the same types of V, D, and J gene segments in T cell receptors and immunoglobulin genes, various identical or related cytokine receptors, TLRs and MHC molecules, etc. However, one notable exception is that HLA molecules are only expressed on activated human T cells and are not present in mice.

There may also be significant differences in post-translational modifications, but this is more difficult to assess comprehensively. Additionally, the structure of immune system-related tissues and organs between humans and mice suggests functional differences, such as the skin, spleen, and thymus. Human skin, for example, is much thicker than mouse skin, with 5-10 cell layers, while mice have only 2-3 cell layers. In terms of exposure to the environment, human life is also much more complicated than that of inbred mice. Since mice are raised under strict SPF conditions to prevent damage to research caused by mouse disease and, if necessary, recaptured by cesarean section to re-acquire the mice, the lack of constant microbial exposure is also a significant concern. Introduced in 1988 by McCune et al. in severe combined immunodeficiency (SCID-Hu), the accurate acquisition of B cell responses remains problematic despite being a "humanized" mouse that faithfully mimics human responses.

Do humans have a new immune mechanism?

It is reasonable to expect that humans may have distinctive immune systems given our low fecundity and our slow sexual maturation. How do we find them if they are out there? 169 genes with different expression patterns between mice and humans may mediate these potential new functions. With the help of the NHLBI website (https://www.nhlbi.nih.gov/), one can also search a very large collection of species data for all known genes. One strategy might be to repurpose genes shared between mice and humans.

Where do we go in the future?

It is undeniable that inbred mice and the incredible technology developed over the past 60 years are a very potent and useful system that will remain a mainstay in the field for some time to come. It is crucial to be able to use mice to study mechanisms and verify hypotheses, even when researching novel human phenomena. However, it is equally crucial to keep in mind the many genetic and anatomical distinctions between humans and mice.

A solution might be to study monkeys, but they are expensive and in short supply. Therefore, the development of tonsil- or spleen-derived human immune organoids may be crucial in enabling the desired mechanistic and hypothesis-driven experiments. A potent method to identify critical genes has also been made available with the introduction of genetic modification using CRISPR/Cas9.

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