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New Insights into the Immune System Using Dirty Mice Sara E. Hamilton, Vladimir P. Badovinac, Lalit K. Beura, Mark Pierson, Stephen C. Jameson, David Masopust and This information is current as Thomas S. Griffith of September 27, 2021. J Immunol 2020; 205:3-11; ; doi: 10.4049/jimmunol.2000171 http://www.jimmunol.org/content/205/1/3 Downloaded from References This article cites 100 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/205/1/3.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. New Insights into the Immune System Using Dirty Mice ,†,‡,x {,‖,# Sara E. Hamilton,* Vladimirx P. Badovinac,x Lalit K. Beura,** Mark Pierson,*x xx Stephen C. Jameson,*,†,‡, David Masopust,†,‡, ,†† and Thomas S. Griffith†,‡, ,‡‡, The mouse (Mus musculus) is the dominant organism then is how to improve the value of experimental rodent re- used to investigate the mechanisms behind complex search to increase the success rate of translating preclinical immunological responses because of their genetic sim- findings to the clinic. One option is for experimental im- ilarity to humans and our ability to manipulate those munologists to supplement existing or developing new models genetics to understand downstream function. Indeed, with variables known or expected to influence the readout, our knowledge of immune system development, re- outcome, and/or conclusions. Unfortunately, it is also fair to sponse to infection, and ways to therapeutically manip- note that most of the envisioned improvements will likely increase the complexity, cost, and, in some cases, limit the ulate the immune response to combat disease were, in Downloaded from large part, delineated in the mouse. Despite the power number of researchers able to fulfill the new model require- of mouse-based immunology research, the translational ments. In this review, we will discuss new insights into im- efficacy of many new therapies from mouse to human munology research using models based on mice with a history is far from ideal. Recent data have highlighted how the of microbial exposure. Humans are exposed to pathogenic and commensal microbes naive, neonate-like immune system of specific pathogen– on a daily basis from birth, which (together with vaccination) http://www.jimmunol.org/ free mice differs dramatically in composition and mature the immune system to provide long-lasting protection function to mice living under barrier-free conditions against future microbial challenge. Immunological memory is (i.e., “dirty” mice). In this review, we discuss major minimal in most mice used in biomedical research because of findings to date and challenges faced when using specific pathogen–free (SPF) housing conditions in contrast to dirty mice and specific areas of immunology research the experienced immune systems of wild mice or mice obtained that may benefit from using animals with robust and from neighborhood pet stores [hereafter collectively referred to varied microbial exposure. The Journal of Immu- as “dirty” mice (4)]. The primary (and most obvious) feature of nology, 2020, 205: 3–11. dirty mice that distinguishes them from traditional SPF labo- ratory mice is that their exposure to multiple mouse pathogens by guest on September 27, 2021 aboratory mouse models represent an undeniable (which are normally excluded under SPF conditions) was asset in our understanding of immunology and hu- found to mature the murine immune system to more closely L man disease. Mice and humans share .90% ge- resemble that seen in adult humans (4–6). It is now appreciated netic homology (1), and their usage has led to the discovery that the baseline status of the immune system can have sig- of a significant number of genes and pathways fundamental nificant implications on the cellular composition and intensity for understanding disease processes and designing effective of subsequent immune responses. Our group published data treatment. Additionally, the power to transfer immune cells outlining the use of dirty mice to evaluate the composition and between hosts, ability to create genetic knockout strains, basic function of the immune system to challenge (compared conditional and inducible deletions, and transgenics are all with SPF mice), but additional work from a number of labo- important advantages to study disease processes within a fairly ratories has reinforced the concept and value of using dirty short timeline. However, many examples now exist whereby mice in preclinical investigation [Table I (4–10)]. Interest- use of the laboratory mouse has misdirected clinical ap- ingly, each publication has used slight variations in method- proaches, failing to positively impact humans and costing ology to generate the dirty mice used for study. The following millions of research dollars in the process (2, 3). The question information will be based on our experience with and data *Department of Laboratory Medicine and Pathology, University of Minnesota, Minne- This work was supported by National Institute of Allergy and Infectious Diseases, apolis, MN 55455; †Microbiology, Immunology, and Cancer Biology Ph.D. Program, National Institutes of Health (NIH) Grants AI116678 (to S.E.H.), AI147064 (to University of Minnesota, Minneapolis, MN 55455; ‡Center for Immunology, Univer- V.P.B.), and AI084913 (to D.M.); National Institute of General Medical Sciences, x sity of Minnesota, Minneapolis, MN 55455; Masonic Cancer Center, University of NIH Grants GM134880 (to V.P.B.) and GM115462 (to T.S.G.); and U.S. Department { Minnesota, Minneapolis, MN 55455; Department of Pathology, University of Iowa, of Veterans Affairs Merit Review Award I01BX001324 (to T.S.G.). ‖ Iowa City, IA 52242; Department of Microbiology and Immunology, University of Address correspondence and reprint requests to Dr. Thomas S. Griffith, Department of Iowa, Iowa City, IA 52242; #Interdisciplinary Graduate Program in Immunology, Uni- Urology, University of Minnesota, MMC 394 Mayo, 420 Delaware Street SE, Minne- versity of Iowa, Iowa City, IA 52242; **Department of Molecular Microbiology and †† apolis, MN 55455. E-mail address: tgriffi[email protected] Immunology, Brown University, Providence, RI 02912; Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN 55455; ‡‡Department of Abbreviations used in this article: CLP, cecal ligation and puncture; SPF, specific xx Urology, University of Minnesota, Minneapolis, MN 55455; and Minneapolis Vet- pathogen–free. erans Affairs Health Care System, Minneapolis, MN 55417 Ó ORCIDs: 0000-0002-3768-7622 (S.E.H.); 0000-0003-3180-2439 (V.P.B.); 0000- Copyright 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 0001-9137-1146 (S.C.J.); 0000-0002-7205-9859 (T.S.G.). Received for publication February 13, 2020. Accepted for publication May 4, 2020. www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000171 4 BRIEF REVIEWS: IMPACT AND FUTURE USE OF DIRTY MICE IN RESEARCH Table I. Mouse models of microbial exposure Model Strengths Weaknesses Human Genetic diversity (outbred) Significant regulations limit in vivo hypothesis-testing studies Experienced immune system Males and females can be used to address sex as a biological variable SPF mouse Can be inbred or outbred Naive immune system Infection history is controllable Microbiome is more uniform Numerous strains readily available to identify and interrogate Can be highly susceptible to pathogens immune cells Male and female mice can be used to address sex as a biological variable Wild mouse Natural pathogen exposure since birth Unknown infection history Diverse microbiome Unknown genetics and age Experienced immune system leads to enhanced protection to Increased cost for dedicated housing new infections Mice must be caught and may carry pathogens dangerous to humans (e.g., hantavirus) Cohoused with pet Can be inbred or outbred Increased cost for dedicated housing (e.g., BSL-3) store mice Can be age-matched with SPF mice Microbial exposure can vary with each cohort Downloaded from Natural pathogen exposure Cohousing can result in death depending on the pet store mouse used Conversion of the naive mouse immune system to a mature/ Unknown variation in microbiome composition effector phenotype is efficient (,10% of cohoused mice experience a poor conversion) and robust Restricted to female mice Sequential infection Infection history is known Requires prior selection of a “correct” set of pathogens http://www.jimmunol.org/ Using known pathogens draws on a larger pool of knowledge Uses laboratory defined routes of exposure instead of natural to interpret results routes Can be done with BSL1- and BSL2-level pathogens Milder conversion than observed with other methods
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