Trends in Immunology
Volume 38, Issue 3, March 2017, Pages 181-193
Journal home page for Trends in Immunology

Review
Making Mouse Models That Reflect Human Immune Responses

https://doi.org/10.1016/j.it.2016.12.007Get rights and content

Trends

A significant contributor to variation in immune responses is bystander infection.

Specific pathogen-free mouse husbandry affects the basal state of the mouse immune system and changes mouse immune responses.

Bystander infections in mice may increase correlation between mouse models and human immune responses.

Humans are infected with a variety of acute and chronic pathogens over the course of their lives, and pathogen-driven selection has shaped the immune system of humans. The same is likely true for mice. However, laboratory mice we use for most biomedical studies are bred in ultra-hygienic environments, and are kept free of specific pathogens. We review recent studies that indicate that pathogen infections are important for the basal level of activation and the function of the immune system. Consideration of these environmental exposures of both humans and mice can potentially improve mouse models of human disease.

Section snippets

Bystander Infections in Mouse Models

Recent work suggests that specific pathogen-free (SPF) husbandry has broad and unexpected effects on the immune system of mice 1, 2. As their name indicates, SPF mice are free of specific pathogens. The list of organisms tested varies from facility-to-facility and room-to-room, but the organisms usually include both disease-causing pathogens and opportunistic and commensal organisms that do not cause disease in healthy mice. Mice raised in SPF conditions represent the benchmark for studies of

Mice As Model Organisms

The mouse model is the cornerstone of biomedical research. The use of genetically inbred strains reduces variability. Researchers can easily manipulate the mouse genome, especially with the implementation of clustered regularly interspaced short palindromic repeats (CRISPR) technology. Mice are easy to breed and economical to house in animal facilities. Through the use of SPF husbandry, microbial exposures can be controlled, further reducing variability. Experimentation in mice has promoted an

Infection History and Variation in Immune Responses

In humans, interindividual variation in immune responses can be driven by nonheritable influences. In a study of monozygotic twins, it was found that nonheritable factors contribute significantly to variation in cell populations, cytokine responses, and serum proteins between individuals [16]. Moreover, genetically identical twins diverge in immune measurements with age, suggesting that environmental factors drive variation. Within this data set, human cytomegalovirus seropositivity was

Infection Modulates Genetics

Genetic ablation of a gene in mice does not always lead to concordance in phenotype compared with genetic deficiency in humans 21, 22, 23, 24. In many cases, immunodeficient mice are more susceptible to a wide range of infections, whereas genetically deficient humans are susceptible to a smaller subset of pathogens. The question is whether this is actually due to disparate functions of these genes in mice and humans, or whether it is due to differences in nonheritable factors between the two

Does Pathogen Exposure Humanize the Mouse Immune Response?

The data described thus far indicate that altered microbiome, as well as infection with chronic and acute pathogens, change immune responses to unrelated pathogens. Now the question is whether these changes are relevant to the comparison between mice and humans. Do laboratory mice that are infected with a diverse set of pathogens have immune responses more similar to human immune responses (Figure 1)? Two recent studies provide evidence that the answer is yes.

The first study compared the immune

What Is the Normal Microflora of a Mouse?

With the expansion of mouse research there has been a push to make mouse facilities cleaner. We have eliminated many of the pathogens commonly found in laboratory animals and wild rodents. Through sentinel monitoring, mouse rooms are tested routinely for a variety of viral, bacterial, and parasitic pathogens. The pathogens that are routinely monitored depend on the facility and the room. A subset of these pathogens is summarized in Table 1. The impetus behind this is a desire to eliminate

Perspective

If we accept that humans and mice have some level of ongoing infection from a variety of pathogens and commensals, then should we change the way we model disease in mice? We think the answer to this is yes. We described just a few of the examples of mouse ‘pathogens’ that regularly infect wild mice. Given the prevalence of many of these organisms in wild mice, and the fact that they often do not cause disease in immunocompetent mice, these mouse ‘pathogens’ may be more accurately classified as

Concluding Remarks

If we consider the multifarious infection history of humans and compare it with the infection history of laboratory mice, it is clear that the ultra-hygienic environment of experimental mice does not recapitulate the environmental exposures of humans. Work from multiple groups now indicates that infection history changes the mouse immune system, and alters the way in which it responds to challenges. Moreover, increasing a mouse’s infection exposure may enhance correlation between mouse and

Acknowledgments

We thank the Reese Lab for helpful discussion, and Julie Pfeiffer for critical review of the manuscript. T.A.R. is the W.W. Caruth Scholar, Jr. Scholar in Biomedical Research and is supported by the Endowed Scholars program at UTSW.

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