Of Mice, Dirty Mice, and Men: Using Mice To Understand Human Immunology

Abstract

Mouse models have enabled breakthroughs in our understanding of the immune system, but it has become increasingly popular to emphasize their shortcomings when translating observations to humans. This review provides a brief summary of mouse natural history, husbandry, and the pros and cons of pursuing basic research in mice versus humans. Opportunities are discussed for extending the predictive translational value of mouse research, with an emphasis on exploitation of a "dirty" mouse model that better mimics the diverse infectious history that is typical of most humans.

Figure 1. Landmark discoveries in immunology

Selections from the American Association of Immunologist's timeline. The species or species-derived material with which experiments were principally performed are indicated by color: human (blue), animal (red), or both human and animal (green).

Figure 2. Practical considerations for research in humans and in mice with varying degrees of immune experience

Humans exhibit significant genetic variability, unlike studies that employ inbred strains of mice. Humans also exhibit significant variability in immunological experience, the effects of which tend to accumulate with age, but also vary by environmental factors. Immune experience in mice can be controlled through diet, sterile derivation, husbandry practices, and sourcing genetically outbred pet store and feral mice from environments outside of biocontainment. These practices impact the cost of mouse studies, sometimes in unexpected ways. For example, while feral mice are cheap to obtain, biocontainment in a lab setting may be quite expensive (institutional costs will vary, and may require ABSL3 housing to protect SPF vivaria from contamination). In general, increased underlying variability increases the complexity of immunologic assays and the cohort sizes needed to test the specific influence of a chosen variable. Thus, reproducible observations may be discoverable in smaller experimental groups of inbred laboratory mice as compared to outbred organisms with heterogenous immune experience. This figure does not highlight technical and logistical considerations that often favor mice (e.g., sample availability, longitudinal studies in tissues, sophisticated approaches that require gene manipulation or a level of invasiveness not permissive in humans), the availability of genetically outbred and outcrossed SPF mice, or the issue that some questions are best addressed in humans (e.g. when the phenomena under investigation is highly species-specific or for which appropriate mouse models have not been developed).