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Immune responses to the real world

Lab Animal volume 47, pages 13–14 (2018)Cite this article

Translation of results obtained from reductionist approaches in rodents to humans is becoming an increasingly vexing issue. A disadvantage of reductionist systems is that conclusions reached under these circumstances are so specific that they fail to translate to more complex (human) systems1. Immunology research in mice is typically performed on genetically defined animals in microbially restricted environments. This approach aims to isolate the effect of the intervention, and mitigate potentially confounding effects of genetic heterogeneity and microbial influences. The major challenge confronting successful translation is to approximate the complexity of human disease in animal experiments, without losing the ability to establish causal relationships. One approach to approximate real-world systems has been to drift away from reductionist norms by introducing greater variability into mouse experiments. A familiar example of this is the argument in favor of using genetically diverse mice over inbred strains. There is growing support for a fundamentally similar argument in support of increasing microbial diversity in mice used for immunology research2,3, with experiments in wild mice4 proposed as a more realistic model of the both the genetic and microbial heterogeneity inherent in most human populations. In this commentary, we discuss changing perceptions of the role of genetics and microbial status in murine models for immunology research.

Use of inbred strains is widespread, in part to reduce variability resulting from genetic heterogeneity. This is accompanied by the drawback that conclusions drawn using inbred animals may not be generalizable to genetically heterogeneous human populations4. Studying phenomena in 'outbred' mice to replicate genomic complexity of human systems has been a subject of debate for decades, particularly in the area of toxicology5. As pointed out by Festing6, the use of genetically undefined 'outbred' Swiss stocks (that derive from a single branch of the mouse family tree) is accompanied by variable and uncontrolled genetic variation that may lead to false negative results. Inbred mice with well-characterized immune-relevant genotypes manifest distinct immunophenotypes7 that facilitate identification of discrete cause-and-effect relationships. Ongoing advances in their genetic characterization continue to enhance their value in dissecting molecular mechanism8,9. However, extrapolating directly from single strains of “laboratory mice” to humans exceeds the intended use of these highly defined genetic tools. Performing the experiment in several different inbred strains6 with informative divergence among genotypes and phenotypes can enhance detection of responses and provide mechanistic insights. Another option is to use Diversity Outbred mice10 in which greater genetic diversity, with input from all seven major branches of the mouse family tree, including the 'wild mouse' group, has been developed, without losing the ability to define and interrogate the genome.

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Authors and Affiliations

  1. Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA

    Caroline J Zeiss

  2. Department of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Cory F Brayton

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  1. Caroline J Zeiss
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Correspondence to Caroline J Zeiss.

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Zeiss, C., Brayton, C. Immune responses to the real world. Lab Anim 47, 13–14 (2018). https://doi.org/10.1038/laban.1384

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