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Immune Relevant Animal Models: Opportunities and Challenges Gregers Jungersen1 and Jorge Piedrahita2

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Immune Relevant Animal Models: Opportunities and Challenges Gregers Jungersen1 and Jorge Piedrahita2 ILAR Journal, 2018, Vol. 59, No. 3, 209–210 doi: 10.1093/ilar/ilz014 Introduction Downloaded from https://academic.oup.com/ilarjournal/article/59/3/209/5560011 by Institute of Medicine Library user on 12 May 2021 INTRODUCTION: Immune Relevant Animal Models: Opportunities and Challenges Gregers Jungersen1 and Jorge Piedrahita2 1Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark; and 2Comparative Medicine Institute, College of Veterinary Medicine, NC State University, Raleigh, North Carolina. *Corresponding Author: Gregers Jungersen, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark E-mail: [email protected]. Abstract Valid interpretation of preclinical animal models in immunology-related clinical challenges is important to solve outstanding clinical needs. Given the overall complexity of the immune system and both species- and tissue-specific immune peculiarities, the selection and design of appropriate immune-relevant animal models is, however, not following a straightforward path. The topics in this issue of the ILAR Journal provide assessments of immune-relevant animal models used in oncology, hematopoietic-, CAR-T cell- and xenotransplantation, adjuvants and infectious diseases, and immune privileged inflammation that are providing key insights into unmet human clinical needs. Key words: animal models; immunology; preclinical validity Animal models are imperative for studies relating to immunology- translate into a better understanding and treatment of clinical related problems because the immune system is a highly immunology-related problems. complex network of different cell types, secreted cytokines, Mice have been instrumental animal models for the enor- chemokines, and other humoral factors that function in an mous advancement of immunological understanding over the organ- or tissue-dependent context that is virtually impossible last decades. The comprehensive review by Radaelli et al [7]pro- to emulate by in vitro studies. Given the large number of vides an updated summary of immune-relevant mouse strains cells, transcription factors, and genetic pathways involved from and stocks as well as mutations and experimental interventions activation to regulation and execution of immune-mediated to induce specific perturbations of the immune system. Careful effectors, the differences between animal species are highly informed selection and use of the numerous mouse models relevant for each and every animal model used for translational will further improve the translational utility, validity, and repro- studies of clinical immunology-related problems. In line with ducibility of research in mice. this, there is a constant debate about the relevance and The prospects of treating cancer by appropriate activation predictive or translational value of immunology-related research of the patient’s own immune system is both appealing and in rodents [1–3] and reproducibility of results obtained from mice highly promising, with cancer immunotherapy being named and other research models is also a well-publicized concern [4,5]. “breakthrough of the year” by the journal Science in 2013. How- These translational challenges eventually lead to premature ever, relevant animal models with high translational validity for clinical trials with current estimates of probability of success of the human clinical setting are scarce. Overgaard et al [8]high- a clinical trial ranging from a minimum of 3.4% for oncology to light the special opportunities in use of spontaneous tumors in a maximum of 33.4% for infectious disease vaccines [6]. dogs and experimental cancer models in pigs to study different In this special issue of the ILAR Journal, the contributors phases of cancer immunoediting in immunocompetent large provide assessments of immune-relevant animal models from animal hosts. small to large that are providing key insights into unmet clinical Although animal models in mice and dogs have been invalu- needs for the advancement of human health. Each article out- able in the development of effective treatment of malignant lines the current state of the art and provides deeper insights and nonmalignant hematological disorders by hematopoietic into a few selected animal models with the most promise to cell transplantation, there are still significant clinical needs to © The Author(s) 2019. Published by Oxford University Press on behalf of the National Academy of Sciences. All rights reserved. For permissions, please email: [email protected] 209 210 Jungersen and Piedrahita address. In the contribution by Graves et al [9], animal models in models from small to large animals. For translational models of mice and dogs are reviewed for their potential to solve the most immune-mediated ocular disease in humans, there are naturally important areas of concern in disease relapse and graft-versus- occurring large animal models, equine uveitis and canine dry host disease in hematopoietic cell transplantation treatment. eye, that have promise to translate into a better understanding Adoptive transfer of engineered chimeric antigen receptor and treatment of noninfectious immune-mediated ocular dis- (CAR)-T cells is a promising therapy for treatment of cancers and eases in humans. chronic viral infections where immunity relies on cell-mediated effector mechanisms. Preclinical studies to predict efficacy and safety of new CAR-T cell developments are not easy to translate References to the human clinic. In this context, Migliorini et al [10]review Downloaded from https://academic.oup.com/ilarjournal/article/59/3/209/5560011 by Institute of Medicine Library user on 12 May 2021 preclinical investigation of CAR-T cells in different humanized 1. Handel AE, Lincoln MR, Ramagopalan SV. Of mice and men: mouse models, in dogs where immune and nonimmune system experimental autoimmune encephalitis and multiple scle- networks are intact, and in nonhuman primate animal models rosis. Eur J Clin Invest. 2011;41:1254–8. with optimal translational relevance to humans for safety eval- 2. Seok J, Warren HS, Cuenca AG et al. Genomic responses in uations. mouse models poorly mimic human inflammatory diseases. Platt et al [11] discuss successes and failures in xenotrans- Proc Natl Acad Sci USA. 2013;110:3507–12. plantation including how immunity functions as a barrier for 3. Takao K, Miyakawa T. Genomic responses in mouse models xenograft acceptance and outlines how the new developments greatly mimic human inflammatory diseases. Proc Natl Acad in genetic engineering of pigs have contributed to dramatic Sci U S A. 2015;112:1167–72. improvement in the outcome of experimental xenografts in 4. Masopust D, Sivula CP, Jameson SC. Of mice, dirty mice, nonhuman primates. The advances in stem cell research has and men: using mice to understand human immunology. J further spurred the development of reverse xenotransplantation Immunol. 2017;199(2):383–8 doi:10.4049/jimmunol.1700453. where human stem cells are transplanted into a pig host and 5. Kafkafi N, Agassi J, Chesler EJ et al. Reproducibility and undergo development and maturation to mature cells, or a tissue replicability of rodent phenotyping in preclinical studies. or an organ, before being transplanted back as an allograft into Neurosci Biobehav Rev. 2018;87:218–32 doi:10.1016/j.neubiorev. the original human donor. 2018.01.003. Advances in vaccine development rely on the selection 6. Wong CH, Siah KW, Lo AW. Estimation of clinical of antigenic targets for the adaptive immune response and trial success rates and related parameters. Biostatistics how these antigens are delivered and presented for the 2019;20(2):273–86 doi: 10.1093/biostatistics/kxx069. immune system. For inactivated and subunit vaccines targeting 7. Radaelli E, Santagostino SF, Sellers RS, et al. Immune infections where a more complex immune response than relevant and immune deficient mice: options and the antibody titer is needed, the adjuvant formulation of the opportunities in translational research. ILAR Journal ily026 vaccine may thus decide the efficacy of the induced antibody doi:10.1093/ilar/ily026. [Epub ahead of print]. response. Schmidt et al [12] review methods for assessing 8. Overgaard NH, Fan TM, Schachtschneider KM, et al. Of humoral and, more difficultly, cell-mediated adjuvant efficacy mice, dogs, pigs, and men: choosing the appropriate and function in animal models. They further highlight examples model for Immuno-oncology research. ILAR Journal ily014 where immune responses in mice poorly correlate with human doi:10.1093/ilar/ily014. [Epub ahead of print]. immune responses and discuss how detailed characterization 9. Graves SS, Parker MH, Storb R. Animal models for preclinical of cellular subset responses in mice may translate to humans. development of allogeneic hematopoietic cell transplanta- To understand the interplay between infectious agents and tion. ILAR Journal ily006 doi:10.1093/ilar/ily006. [Epub ahead both innate and adaptive host immune responses, appropriate of print]. animal models for the individual infectious agents must also 10. Migliorini D, Mason NJ, Posey AD. Keeping the engine be carefully selected. Starbæk et al [13] review virus receptor running: the relevance and predictive value of preclini- distribution and host anti-viral protein responses in different cal models for CAR-T cell development. ILAR Journal ilz009 animal models for the studies of Influenza A virus with a special doi:10.1093/ilar/ilz009. [Epub ahead of print]. focus on pigs
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