C H A P T E R
27 Animal Models of Organ-Specific Autoimmune Disease Ken Coppieters1, Matthias von Herrath2 and Dirk Homann3 1
Global Research, Research Project Management, Ma˚løv, Denmark 2Type 1 Diabetes Research Center, Novo Nordisk, Seattle, WA, United States 3Icahn School of Medicine at Mount Sinai, New York, NY, United States
O U T L I N E What Can Animal Models Teach Us About Organ-Specific Autoimmunity? Animal Models in Basic Science: Understanding the Complexity of Organ-Specific Autoimmunity Animal Models in Drug Development: Picking the Winners Summary of Advantages and Disadvantages of Animal Models A Survey of Animal Models for Organ-Specific Autoimmune Diseases Hashimoto’s Thyroiditis and Graves’ Disease Type 1 Diabetes Addison’s Disease Celiac Disease
Pernicious Anemia Ulcerative Colitis and Crohn’s Disease Autoimmune Hepatitis Primary Biliary Cirrhosis Vitiligo Alopecia Arreata Dermatitis Herpetiformis Multiple Sclerosis Narcolepsy Immune Thrombocytopenic Purpura Giant Cell Arteritis
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The problem of science will consist precisely in this, to seek the unitary character of physiological and pathological phenomena in the midst of the infinite variety of their particular manifestations. Bernard (1865). All models are wrong but some are useful. Box (1979).
WHAT CAN ANIMAL MODELS TEACH US ABOUT ORGAN-SPECIFIC AUTOIMMUNITY? Throughout recorded history, animals have claimed a principal place in our imagination and inspired a broad range of practices that substantially shaped the course of our collective pursuit to organize and control the natural world. Based on the notion that humans and other animal species apparently share certain anatomic and physiological characteristics, the heuristic use of animals to specifically address questions about human health and disease emerged at least 2500 years ago and the potential, limitations, and ethical implications of “animal The Autoimmune Diseases, 6th. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00027-0
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experimentation” have been discussed ever since (Ericsson et al., 2013; Franco, 2013). The related concept of “animal model” can therefore draw on a rich history of practical and discursive exploration but its actual formalization emerged only in the late 20th century and includes the proposed definition of “a living organism in which normative biology or behavior can be studied, or in which a spontaneous or induced pathological process can be investigated, and in which the phenomenon in one or more respects resembles the same phenomenon in humans or other species of animal” (CMBR, 1985; Hau, 2003; Held, 1980; Wessler, 1976). The contemporary concretization of these ideas further integrates the ethical core principles that build on Russell and Burch’s original “3Rs” (replacement, reduction, and refinement) as a guide for animal studies and that continue to evolve to meet the concerns and challenges arising from an ongoing effort to balance the importance of empiric and value judgments (Tannenbaum, 2017). Since “the definitions of key concepts used in any scientific endeavor express the fundamental aims and priorities of that endeavor” (Tannenbaum and Bennett, 2015), it is within this larger context that animal models for organ-specific autoimmune diseases have to be considered (Cohen and Miller, 1994; Morel, 2004; Taneja and David, 2001; Wekerle et al., 2012; Williams, 2010; Yu et al., 2015). We submit that beyond the practical aspects of harnessing animal models for the study of specific autoimmune disorders, a historically and epistemologically informed perspective ultimately will precipitate the development of more productive research practices by allowing for more accurate diagnoses of current shortcomings and better prescriptions for needed course corrections. In what follows, we will first sketch out examples of scientific questions that are typically answered with the aid of animal models before embarking on a broad survey of their use and utility for the study of major organ-specific autoimmune diseases.
Animal Models in Basic Science: Understanding the Complexity of Organ-Specific Autoimmunity Arguably the most important and certainly most obvious path toward an improved and actionable understanding of organ-specific autoimmune diseases is the combination of clinical observation and intervention as well as experimentation with human blood and/or tissue samples. In as much as certain aspects of pathogenesis and pathology can be reproduced in animal models, such experimental strategies may complement and expand the scope of interrogation beyond the restrictions of human tissue access, availability, and ethical considerations; relevant observations and insights may then in turn inform and guide further human research endeavors. These “dialogical dynamics” of human and animal model research, including their possible pitfalls, are readily illustrated by the history of type 1 diabetes (T1D) research over the past half-century. The conception of T1D as an autoimmune disease in the mid-1970s emerged in the wake of seminal discoveries made primarily through investigations of the human disease (inflammatory infiltrates affecting the pancreatic islets, islet cell antibodies, HLA associations) and provided the impetus for the subsequent development of suitable animal models (Gale, 2001). However, the relative ease and success with which the animal models supported, refined, and enriched the autoimmune hypothesis over the ensuing three decades also detracted from the further pursuit of the logistically, practically, and ethically more challenging interrogation of the human pancreas. Only more recent assessments have emphasized the inherent limitations of in vivo T1D models, their potential to promote a biased or even distorted understanding of the disease process, and the importance to realign preclinical investigations according to relevant pathogenetic parameters of the human disease (Roep, 2007; von Herrath and Nepom, 2009). As a consequence, interest in the detailed histopathology of the pre/diabetic human pancreas has been rekindled (Morgan et al., 2014; Richardson et al., 2014), and its pursuit greatly facilitated by the creation of initiatives such as the Network for Pancreatic Organ Donors with Diabetes (nPOD), a T1D tissue repository that collects, processes, and distributes pancreatic tissues to accredited T1D research teams (Campbell-Thompson et al., 2012; Kaddis et al., 2015). The direct study of the diseased organ can now provide an important referent and corrective for future studies of accessible human tissues such as peripheral blood, and for the more effective and adjusted use of T1D animal models. Disease-specific and technological constraints further define the potential scope of experimental exploration; here the fact that biopsy of the human pancreas is difficult, risky, raises ethical concerns, and, given the regional and lobular distribution of the pathological processes as revealed in recent nPOD studies, may not necessarily capture representative biological material (Atkinson, 2014; Gianani et al., 2010; Krogvold et al., 2014). Even when human tissue samples are readily accessible, interpretation of experimental results can be difficult due to the lack of tissue or organism context. Let’s take as an example here intestinal diseases such as Crohn’s disease (CD), where biopsies are relatively easily obtained. Even under the best possible culturing conditions, how can an isolated slice of intestinal epithelium faithfully reproduce the milieu of the T cells it harbors? Stress responses, disrupted interactions with microbiota, altered gravitational, and osmotic conditions are only a few of
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the confounding factors. That is not to say that one cannot obtain valuable data from these ex vivo systems. But some type of validation within the context of a living organism is typically required to corroborate the physiological validity of such findings. This applies particularly to results obtained using human-derived cell lines, which represent often aberrantly functioning clones from a single cell, from a single organ, and from a single individual, thus missing even the slightest organismal context. Animal models have helped us to understand the complexity of autoimmune disease processes by partially replicating these conditions within an organismal context. This is an important notion, as it acknowledges that no animal model should ever be studied in isolation. Chemically destroying the intestinal barrier, for example, will reproduce certain mechanisms associated with cellular stress, altered microbial sensing, and tissue repair as observed in inflammatory bowel diseases (IBDs) (Chassaing et al., 2014). It will not, however, provide information the primary role of regulatory T cells (Tregs) in maintaining immune homeostasis in the gut, for which a Tcell transfer model would be more suitable (Eri et al., 2012). In other words, our understanding of human disease has historically been built on the combined datasets emerging from work on cell lines, primary cells, tissues and organ cultures, and all available animal models. Neither a single human explant study nor a particular animal model should be relied upon to generate a complete picture because each has its specific limitations. In the immunogenetic arena, animal models have provided particularly useful insights. Genome-wide association study (GWAS) technology has revealed a tremendous degree of detail on the array of genes associated with human autoimmune diseases. Gene-function relationships are extremely difficult to study in humans and genetically modified animals have historically filled that void. The role of the IL-10 pathway in IBD (Kuhn et al., 1993), interferon signaling in multiple sclerosis (MS) (Chu et al., 2000), and insulin autoreactivity in T1D (Nakayama et al., 2005) are examples where transgenic animals have elucidated what are now believed to be the key aspects of the immunopathology. Moreover, broad concepts that apply to multiple forms of autoimmunity have been discovered or characterized in mice, with AIRE-mediated thymic T-cell selection (Anderson et al., 2002) and Foxp3-regulated natural Treg development and function (Hori et al., 2003) being prime examples. Overall, the comparison between mouse models and humans deficient in respective genes greatly contributes to our understanding of autoimmunity, even if complete phenotypic homology between knockout mice and the respective human genetic deficiency is often lacking. Finally, despite intensive research over the last few years, there are some crucial elements in organ-specific autoimmunity that we are yet to fully comprehend. One major problem is that for many organ-specific autoimmune diseases, we still do not know the targets of the initial autoimmune response, although in others such as in pemphigus vulgaris (Lin et al., 1997), myasthenia gravis (Fambrough et al., 1973), and autoimmune gastritis (Karlsson et al., 1988), the driving autoantigen has been defined. This is a research question which needs to originate from or at least be confirmed by human studies, not animal models. The same applies to studies on inciting environmental factors, where epidemiological studies have much more relevance and power. Ideally, animal models should then be designed based on that knowledge. We believe that human polygenic autoimmune diseases are likely triggered by a wide variety of environmental factors in individual patients, making it unlikely that we will ever be able to define a single or a small set of environmental risk factors. We should therefore rather focus on common downstream disease pathways, for which animal models are excellent tools.
Animal Models in Drug Development: Picking the Winners During the course of commercial drug development, animal models are primarily used during the early discovery phase to support drug targets for further progression into the pipeline. The important decision to select drug targets for progression toward further analog design and screening is rarely ever based on the outcome of a single animal model. Typically, the criteria for progression involve genetic association, target protein, or mRNA association in human disease tissue, in vitro and ex vivo human cell or tissue experiments demonstrating beneficial responses, and, in addition to all of this, successful treatment with a research lead molecule in multiple animal models. There are some general preferences in the drug industry when it comes to the use of animal models. Firstly, experimental disease should be reliably induced or occur spontaneously within a predictable time period and should exhibit a reproducible disease phenotype. A popular animal model for rheumatoid arthritis (RA) for instance is the collagen-induced arthritis (CIA) model in DBA/1 mice (Brand et al., 2007), because it fulfills these criteria and can thus be used in a relatively high-throughput in vivo screening approach. A variant of the model, induced with autologous collagen, may well mimic the remitting relapsing course of RA better, but it takes much longer to induce, shows more variability, and has therefore never really enjoyed widespread use (Malfait et al., 2001).
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Secondly, models with an established track record of translatability are favored. Returning to the CIA example, we have long known that standard-of-care biological therapies such as anti-TNF agents reproducibly alter the model’s disease course (Williams et al., 1992). So, even though the acute nature of the model may not faithfully reproduce human disease, many drugs that are efficacious in humans can serve as positive controls for experimental compounds. On the contrary, many have argued that the nonobese diabetic (NOD) model for diabetes has proven unreliable in predicting clinical translatability, although we would argue that perhaps the model has historically not been used correctly. One example in the T1D arena is CTLA-4-targeted therapy, which is able to prevent diabetes in the NOD mouse when given early but is incapable of reversing clinical disease (Lenschow et al., 1995). In a subsequent clinical trial, 2-year continued administration in recently diagnosed patients was only effective in the initial months of treatment, which to some extent serves to confirm what was predicted by the animal data (Orban et al., 2011). Thus the choice of drug and trial design does not always seem to be rationally based upon animal research and is often more governed by the availability of certain drugs. Thirdly, a robust understanding of the model’s disease mechanisms is required to enable proper usage. Sticking with the CIA example, one could argue that after decades of use, there is substantial information available on every imaginable gene, cell, or protein that drives the disease process (Luross and Williams, 2001). We know that the eventual effector mechanisms are multifaceted and to some extent redundant. Asking the original question of whether TNF plays a primordial role in this model makes sense and the result of those experiments supported the medical hypothesis that spurred the development of anti-TNF biologicals for RA. Likewise, it would be suitable to study agents affecting the IL-6 pathway (Alonzi et al., 1998), currently a major class of drug target in RA. It would, however, not make sense in our opinion to treat animals that transgenically overexpress TNF with a TNF inhibitor because that result would not be very informative based on the fact that the mechanism is known to be primarily driven by TNF. That would be stacking the deck in favor of the therapy under observation. When all these criteria are fulfilled and the experimental approach is planned, we cannot stress enough the need for properly powered study designs and sufficient numbers of experimental repetitions. Not a single animal model we know of doesn’t show at least some degree of heterogeneity, be it in disease penetrance, progression rate, or severity. Even relatively subtle environmental changes can cause alterations in for instance the colony’s microbiome, leading to variations in disease development. Nevertheless, rather than trying to control all possible variables in order to achieve reproducible drug effects, one should expect a sufficiently potent drug to confer mildly variable levels of protection regardless of environment, animal vendor, injection volume, etc. We have evaluated preclinical intervention strategies developed by others that are reproducible only if all of the aforementioned parameters are precisely controlled. When the ultimate aim is to take robust treatment strategies to an outbred human population, with vastly differing environmental conditions and notoriously heterogeneous disease courses, treatment efficacy contingent on tightly controlled conditions constitutes a considerable limitation (Harris, 2017). An example of a theoretically attractive niche where animal models still have to deliver on predictive potential is the area of antigen-specific therapies (Coppieters et al., 2012b). This treatment approach holds significant promise since it specifically targets only immune cell subsets responsible for disease pathogenesis rather than inducing generalized immunosuppression with its associated complications. From a translational angle, it is still unclear whether tolerizing the “driver” T-cell clones would be sufficient to reverse an ongoing autoimmune process and has therapeutic value. Some reports suggest a striking oligoclonality, which in turn indicates that deletional immunotherapy using one or a few autoantigenic determinants might be feasible (Hafler et al., 1988; Kent et al., 2005). Animal models also suggest that T-cell receptor (TCR) avidity plays a pivotal role, as it was shown that low-avidity clonotypes can act protectively (Han et al., 2005). Numerous other reports, however, suggest that low-affinity clones might in fact be the driving force. For example, in the slow-onset variant of the RIP-LCMV model (mice susceptible to T1D after lymphocytic choriomeningitis virus infection due to transgenic expression of LCMV proteins under control of the rat insulin promoter), low-affinity T cells are responsible for disease induction (von Herrath et al., 1994). In human T1D, similar conclusions were drawn from studies using a preproinsulin-specific human CD8 T-cell clone that is capable of inducing beta cell death (Skowera et al., 2008). Remarkably, the TCR of this clone was of extraordinarily low affinity, redefining the understanding of what constitutes a functionally relevant TCR pMHC interaction (Bulek et al., 2012). Within that framework of knowledge, animal models have been used to evaluate antigen-specific therapies that have now completed early clinical trials, including proinsulin plasmid (Roep et al., 2013), peptide therapies (Alhadj Ali et al., 2017), and oral insulin (Bonifacio et al., 2015; Greenbaum, 2017) for T1D. The jury is still out on the former two approaches with only safety data being available, while the book can probably be closed on the latter. In fact, we recently attempted to elicit antigen-specific tolerance using oral insulin of various sources, formulations, and doses but failed to generate support for robust efficacy (Pham et al., 2016).
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Finally, one interface between discovery research and clinical development that may benefit from animal model research is the field of biomarker discovery. Well-characterized animal models are suitable tools to pose questions that often cannot be asked in humans, such as whether peripheral blood cell populations reflect the events at the target organ, change in response to therapy, or correlate with therapeutic benefit. One could then take such mode-of-action-related biomarkers into Phase 1 trials to assess whether they can be reliably measured and then correlate levels to efficacy in Phase 2 proof-of-concept trials. Again, rather than offering ultimate proof, animal models should be seen as part of the hypothesis generation, which ultimately would be tested in the clinic.
Summary of Advantages and Disadvantages of Animal Models As illustrated in Box 27.1 and as outlined earlier, there are several areas of investigation, where we have learned much from animal models of organ-specific autoimmunity. The first is the investigation of immune responses at locations that are inaccessible in humans. Moreover, in these diseases, much of what we know has often been derived from peripheral blood samples but it is unclear how this correlates to immune status at the target organ. We, for instance, were able to pioneer the in vivo visualization of immune responses at cellular resolution in the mouse pancreas during the development of autoimmune diabetes (Coppieters et al., 2012a); such information can not be gathered in the human target organ with any of the technologies currently available. It is difficult to establish the proof of concept in humans. Many techniques that are frequently used to unequivocally identify cellular subsets that are important in the etiology or progression of autoimmunity are impossible to implement in a clinical setting. Examples include adoptive transfer experiments, knockout technologies, bone marrow chimeras, and many more. Accordingly, the continued and refined use of animal models remains at present indispensable to provide initial preclinical support for novel drugs and to define suitable dose ranges and regimens for immunotherapies. How far reaching should the conclusions that we draw from observations in a given animal model be? The prevailing approach in scientific communication is still that a discovery in one of the animal models thought to faithfully represent the human disease is sufficient for acceptance for publication. If the same result is found in a subsequent submission, it is typically considered “confirmatory;” if a different result is discovered, the “secondary” model is frequently labeled as not-as-good or even flawed, for which various reasons are cited. This, we believe, can be treacherous and may hamper the translation of research performed in animal models, because our pathogenetic insight into human diseases is often still rather limited due to ethical constraints. For example, only about 10% of patients with T1D exhibit the same clinical features as the NOD diabetic mouse, which is characterized by a polyglandular autoimmune syndrome affecting thyroid, salivary glands, and testes (Atkinson and Leiter, 1999; Roep et al., 2004). However, there are also striking similarities between NOD and human diabetes, for example, the occurrence of autoantibodies that precedes the development of clinical disease in NOD mice and humans (Pietropaolo and Eisenbarth, 2001).
BOX 27.1
W H AT C A N A N I M A L M O D E L S T E A C H U S T H AT W E C A N N O T L E A R N O T H E RW I S E ? • In vivo immune kinetics at sites that are difficult to access in humans. • Proof of concept using techniques that cannot be used in humans, such as adoptive transfers, genetic knockouts, bone marrow chimeras, etc. • Preclinical drug validation, large-scale assessment of dose range, toxicity, and immunization sites in drug and vaccine development.
• A single model is unlikely to cover all aspects of human pathology; concepts should therefore ideally be confirmed in multiple models. • Genetic knockout models do not mimic the subtle and complex genetic imbalances that are thought to underlie human diseases. • Environmental factors are usually not known and thus cannot be mimicked.
Reasons to be cautious with animal data:
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We can now be certain that one single genetic defect or polymorphism will not be the cause for most human autoimmune disorders. We have learned from the multitude of GWAS that the far more common scenario is a substantial degree of polygenic complexity. This is likely to involve many protective and predisposing genes that act in concert, leading to disease manifestation in a fraction of their bearers. In addition to major histocompatibility complex (MHC) class II molecules that are found in association with several organ-specific autoimmune diseases such as MS and T1D, many less frequent polymorphisms in immune-related genes contribute to the expression of autoimmune disease (Bluestone et al., 2010). Immunogenetic studies in genetically identical mice can therefore not be expected to fully mimic the diverse array of polymorphisms that lead to disease in genetically distinct human subjects. Thus, seeking direct relevance to the human disorder becomes very important, and the assumption that there is a necessity to identify genetic defects in animal models in order to obtain the best pathways to cure human disease may not be correct. Indeed, in today’s medicine, there is little evidence that the optimal treatment for a given disease is always the elimination of its cause. However, immunogenetics in animal models might still help the adoption of novel predictive strategies and subclassifications for autoimmune diseases, which may in the future allow for more individualized treatments. Finally, most of these genetic associations are weak enough to allow for the possibility that environmental factors in addition to genetic determinants precipitate penetrance of disease. These factors, however, are poorly defined in most organ-specific autoimmune diseases. In the NOD mouse, for example, there appears to be a role for the gastrointestinal microbiome (Wen et al., 2008), although under normal specific pathogen-free conditions, diabetes develops without the need for an external stimulus. In human T1D, the strongest evidence for a potential trigger points toward enteroviral infection (Yeung et al., 2011). While viral infection can also accelerate disease in the NOD model under certain conditions, it is normally not required for onset. It is thus obvious that the NOD model does not faithfully integrate the environmental factors that seem to characterize the human disease. Similar discordances are present in models for MS, where neuronal antigens are often injected in adjuvant to induce demyelinating disease. Such nonphysiological conditions should always be kept in mind when interpreting results from animal models.
A SURVEY OF ANIMAL MODELS FOR ORGAN-SPECIFIC AUTOIMMUNE DISEASES Parsing animal models for organ-specific autoimmune diseases is a taxonomic exercise that readily evokes the “ambiguities, redundancies, and deficiencies” so brilliantly illustrated by Borges in his “Celestial Emporium of Benevolent Knowledge”, an apocryphal classification of the animals that distinguishes, amongst others, “those that belong to the emperor”, “those that are included in this classification”, “those that have just broken the flower vase”, and “those that, at a distance, resemble flies” Borges (1942). So, while the basic distinction between “spontaneous” and “induced” autoimmune disease models appears sensible (Hau, 2003), the oft-used addition of “genetically engineered animals” as a third category generates a logical conundrum since genetic manipulation may of course be employed to refine existing or create new models for both spontaneous or induced autoimmune disease. Additional subdivisions such as those made according to inducing agents can be equally confounding [proteins/peptides and adjuvant, pathogens, specific immune effectors (antibodies or T cells), chemicals, etc.], some “proof-of-principle” demonstrations may exude a whiff of circular logic [e.g., combining tissue-specific expression of “neo-autoantigens” with TCRtransgenic (TCRtg) T cells recognizing that very antigen], and certain interventions may stretch the limits of what can be considered autoimmunity (e.g., toxin-induced destruction of selected target tissues); all of this poses a challenge to constructive classification, yet it also constitutes a celebration of the manifold and at times wondrous combinatorial possibilities afforded by experimental autoimmunology. Since the topic of our survey therefore proves somewhat resistant to a convincing organization of its constituents, namely, the relevant animal models available for study of organ-specific autoimmune diseases, we have aimed to avoid an otherwise arbitrary selection of models for further discussion by grounding our choices in a ranking of human autoimmune diseases according to their overall prevalence (Hayter and Cook, 2012). Building and expanding on just a few earlier reports, Hayter and Cook identified 81 human autoimmune diseases that together affect an estimated B4.5% of the population; 23 autoimmune diseases can be considered as “non-rare” (i.e., present at a frequency of .1/ 10,000) and of these, 17 are classified as organ specific (Table 27.1). In terms of prevalence, these 17 organ-specific diseases represent B75% of all autoimmune disorders, and we provide here a brief overview of the corresponding animal models developed to emulate and study these conditions a clear majority of which (B80%) involves endocrine or digestive systems. For a more detailed discussion of the various diseases and their in vivo models, the reader is referred to respective review articles cited later as well as the disease-focused chapters in this book.
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TABLE 27.1
The Most Common Organ-Specific Autoimmune Diseases in Humans Prevalence
Organ system
Organ-specific autoimmune disorder
(per 105)
Ratio F:M
Endocrine system
Hashimoto’s thyroiditis (HT)
791.7
19:1
Digestive system
Celiac disease
750.0
1.3:1
Endocrine system
Graves’ disease (GD)
629.0
7.3:1
Endocrine system
Type 1 diabetes (T1D)
480.0
0.8:1
Integumentary system
Vitiligo
400.2
1.1:1
Digestive system
Pernicious anemia/autoimmune gastritis
150.9
2.0:1
Integumentary system
Alopecia areata (AA)
150.0
1.0:1
Hematopoietic system
Immune thrombocytopenic purpura (ITP)
72.0
2.3:1
Nervous system
Multiple sclerosis (MS)
58.3
1.8:1
Nervous system
Narcolepsy
30.6
0.6:1
Cardiovascular system
Giant cell arteritis (GCA)/temporal arteritis
30.0
5.7:1
Digestive system
Ulcerative colitis (UC)
30.0
1.9:1
Digestive system
Crohn’s disease (CD)
25.0
0.7:1
Digestive system
Autoimmune hepatitis (AIH) types 1 and 2
19.9
3.6:1
Digestive system
Primary biliary cirrhosis (PBC)
14.6
8.1:1
Endocrine system
Addison’s disease (AD)
14.0
1.7:1
Integumentary system
dermatitis herpetiformis (DH)
11.2
0.6:1
Modified from Hayter, S.M., Cook, M.C., 2012. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun. Rev. 11, 754 765.
Hashimoto’s Thyroiditis and Graves’ Disease Thyroid-specific autoimmunity covers the spectrum from hypo- [Hashimoto’s thyroiditis (HT)] to hyperthyroidism [Graves’ disease (GD)] and preferentially targets thyroglobulin, thyroid peroxidase, and the thyroidstimulating hormone receptor (TSHR). Antibodies and T cells specific for these autoantigens are detected not only in HT and GD patients but also healthy individuals reinforcing the concept that autoimmunity in fact represents a continuum stretching from the physiological to the pathological (Coppieters et al., 2013). Of historical interest is a series of studies conducted by Rose and Witebsky in the mid-1950s that explored the consequences of immunizing rabbits with leporine thyroid extracts in adjuvant and that noted the generation of autoantibodies and mononuclear thyroid infiltrations (Rose and Witebsky, 1956; Witebsky et al., 1957); this observation was complemented by the parallel demonstration of Roitt et al. (1956) that sera from HT patients contain thyroglobulin-specific autoantibodies. The work of Rose and Witebsky not only paved the way for the development of “experimental autoimmune thyroiditis (EAT)” to model the most common of organ-specific autoimmune diseases but in fact changed the course of autoimmune research at large by finally, if reluctantly, rejecting a persistent misreading of P. Ehrlich’s half-century old “horror autotoxicus” (Silverstein, 2009). EAT is readily induced in genetically susceptible mice by immunization with thyroglobulin (and more recently also with thyroid peroxidase), following neonatal thymectomy in certain mouse and rat strains, after transfer of specific T cells but not antibodies, and through various other modulations of T-cell immunity. In addition, spontaneous thyroiditis occurs in several species including obese strain chickens, biobreeding (BB) rats, and NOD mice lacking the chemokine receptor CCR7 or expressing the H-2Ak allele (the latter mice are diabetes-resistant, spontaneous disease is exacerbated by dietary iodine and reproduces hallmarks of HT such as high titers of TG antibody and cellular infiltration of the thyroid). Altogether, these models have contributed to the identification of genetic, cellular, molecular, and environmental pathogenesis determinants, have established HT as a paradigm for other T-cell-mediated organ-specific autoimmune diseases, and have provided fundamental insights into peripheral tolerance mechanisms by
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precipitating the second wave of regulatory T-cell research (Kong et al., 2009; Ludgate, 2008; Nagayama and Abiru, 2011; Stassi and De Maria, 2002). For historical, conceptual, and practical reasons, the strategies to model HT therefore occupy a role unlike any other in the field of autoimmunity research. In contrast, a truly satisfactory GD model has not yet been established. An autoimmune condition apparently unique to humans, GD is caused by agonistic TSHR-specific antibodies that mimic the action of TSH and drive uncontrolled thyroid hormone production. No spontaneous GD model exists, and traditional protein/adjuvant approaches to TSHR immunization have failed to promote hyperthyroidism. Over the past 20 years, several GD models have been developed that are all based on immunization against and, in vivo expression of, the TSHR; they can be broadly divided into injection of TSHRexpressing cells and genetic immunization with TSHR-DNA plasmids or recombinant adenoviral vectors. Overall, the A-subunit of TSHR is more efficient in inducing disease than the holoreceptor, and more recent methodological refinements employing repetitive adenoviral vaccinations or the in vivo electroporation of TSHR expression plasmids have succeeded in reproducing some aspects of Graves’ orbitopathy (McLachlan et al., 2005; Moshkelgosha et al., 2015; Nagayama et al., 2015; Wiesweg et al., 2013).
Type 1 Diabetes In a notably broad array of animal models, hyperglycemia or T1D-like disease develops either spontaneously or in the wake of chemical, surgical, infectious, and/or genetic manipulations (Chatenoud, 2008; King and Austin, 2017; King, 2012; Van Belle et al., 2009). Streptozotocin (STZ) and alloxan are toxic glucose analogs (Lenzen, 2008) routinely used to model end-stage disease in rodents for the purpose of testing drugs (e.g., new insulin formulations) and interventions (e.g., islet transplantation) that specifically aim to lower blood glucose. An important and perhaps underused alternative to chemical T1D induction is the Akita mouse that exhibits hypoinsulinemia and pronounced hyperglycemia as a consequence of an insulin 2 gene mutation, overload with misfolded proteins and resultant ER stress. Hyperglycemia may also be induced in pigs and nonhuman primates through tailored STZ treatment or pancreatectomy but all of the preceding approaches obviously are of limited value for the elucidation of genuine autoimmune processes. Certain viral infections (coxsackie B virus, encephalomyocarditis virus, and Kilham rat virus) may promote direct and/or immune-mediated beta cell destruction, and transgenic expression of model antigens in beta cells [ovalbumin, influenza hemagglutinin, or LCMV glycoprotein (LCMV-GP)] renders them susceptible to attack by TCRtg T cells specific for the same antigens. Of these models, the LCMV-GP and related mouse strains are particularly useful since T1D can also be induced following LCMV infection and efficient beta cell destruction by the endogenous virus-specific T-cell response (Ohashi et al., 1991; Oldstone et al., 1991). Collectively, the transgenic models offer a substantial degree of experimental freedom that greatly facilitates the visualization, quantification, characterization, and manipulation of antigen-specific, diabetogenic T-cell immunity and, in particular, allows for a thorough interrogation of pathogenic mechanisms and potential therapeutic interventions. However, the models do not feature the gradually accumulating, diversified, and endogenous beta cell antigen-specific and mostly low-affinity T-cell populations present in T1D patients; they do not capture aspects of genetic susceptibility other than the engineered components; and, in the absence of TCRtg T cells, they do not develop spontaneous or even peptide/protein immunization-induced disease. The latter observations support the general conclusion about the not inconsiderable challenges to break peripheral tolerance and bolster the importance of spontaneous T1D models. The four major models in this category are the NOD mouse and three rat strains (BB, Komeda diabetes-prone, and LEW.1AR1-iddm rats) (King and Austin, 2017; Lenzen, 2017; Whalen et al., 2001); other spontaneous T1D models such as canine autoimmune diabetes may offer distinct advantages in terms of pathophysiological similarities with the human disease but are otherwise not widely employed (O’Kell et al., 2017). The NOD mouse was discovered in Japan in 1974, introduced to the public in 1980, and by 1987 had become a fully established T1D model (Tochino, 1987). Since then, some 11,000 articles have been published (corresponding to an average of one publication per day over the past 30 years) making the NOD mouse the most widely studied autoimmune disease model. In these mice, a slow and seemingly stochastic progression from initial insulitis to beta cell destruction culminates in frank hyperglycemia by 30 weeks in B80% of females and B30% of males; T1D development is affected by various husbandry practices, “cleanliness” of the facility, viral infections, and intestinal microbiota (King and Sarvetnick, 2011; Paun et al., 2017; von Herrath et al., 2011) and therefore overall disease incidence may vary substantially in different mouse colonies. Immunopathogenetically, a complex interplay of T and B cells, dendritic cells, macrophages, and NK cells initiates and perpetuates spontaneous T1D in NOD mice, and various approaches can accelerate disease onset for practical purposes (cyclophosphamide injection, diabetogenic T-cell transfer, islet transplantation to
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overtly diabetic recipients). Because of its remarkable breadth and depth, the cumulative delineation of genetic, pathologic, and immunologic factors in NOD diabetes as well as the development of multiple effective prophylactic and therapeutic interventions (Chaparro and Dilorenzo, 2010; Shoda et al., 2005) constitutes a fundamental and fascinating contribution to T1D research and beyond. The seeming failure to translate these insights into treatment modalities for human T1D, however, has caused an early backlash and of late an abundance of discussions that attempt to reassess the potential and limitations of NOD research from a translational perspective (Driver et al., 2011, 2012; Graham and Schuurman, 2015; Pearson et al., 2016; Reed and Herold, 2015; Roep et al., 2004; von Herrath and Nepom, 2009). The arguments are overall nuanced; the utility of NOD (and other preclinical T1D) models has to be ascertained in an appropriate, detailed, and highly context-specific manner; and among the promising recommendations is an increased investment in humanized mouse models (Serreze et al., 2016). Lastly, it should be noted that the profound immune dysregulation in NOD mice (Anderson and Bluestone, 2005) is not restricted to promotion of beta cell destruction and can affect multiple other organ systems such that wild-type, congenic, transgenic, and/or immunodeficient NOD mice may be harnessed for the study of other major organ-specific autoimmune diseases [HT, Addison’s disease (AD), celiac disease, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), dermatitis herpetiformis (DH), and MS] as well as autoimmune cholangitis, sialadenitis, orchitis, neuritis, and other conditions.
Addison’s Disease Throughout the second half of the 20th century, various attempts to model AD employed the immunization of guinea pigs, rabbits, rats, or mice with adrenal extracts and adjuvant. Collectively, “experimental autoimmune adrenalitis” emulates the aspects of the human disease (lymphocytic infiltration of adrenal glands, autoantibodies) and emphasizes the dominance of cell-mediated autoimmune processes (adoptive transfer of cells but not serum from immunized rodents causes adrenalitis in recipients) but remains of limited value due to the different histopathological presentation of adrenal lesions, their transient nature, and, with only two exceptions, a lack of adrenocortical insufficiency; similar considerations apply to the “spontaneous” lymphocytic infiltrations observed in NOD mice in the absence of clinical disease (Betterle et al., 2008; Bratland and Husebye, 2011). In contrast, both cats and dogs can develop spontaneous symptomatic AD (accompanied by adrenal infiltrations but usually not autoantibodies) and the identification of orthologous genetic susceptibility loci in canine and human AD suggests a common underlying autoimmune etiology (Mitchell and Pearce, 2012). In an interesting twist to animal experimentation, however, human AD studies appear to have been useful for research in dogs but not vice versa (Mitchell and Pearce, 2012), and a genetically well-defined, robust AD model remains to be developed.
Celiac Disease Defined as an autoimmune enteropathy induced by dietary gluten in genetically predisposed individuals, “spontaneous” celiac disease is also observed in Irish Setters, Rhesus macaques, and horses (Marietta and Murray, 2012). However, since the utility of these animals as research models is restricted by unclear or nonexistent disease associations with MHC-II genes (the main risk factor in humans) as well as practical and ethical considerations, considerable effort has been invested in the development of suitable murine models (Costes et al., 2015; Korneychuk et al., 2015; Verdu et al., 2015). Collectively, however, studies conducted with wild-type, immunodeficient, and especially humanized mice expressing HLA-DQ2.5 or -DQ8 haplotypes and challenged with gluten containing diet or gliadin have been hampered by the robust tolerance to food antigens in rodents. Accordingly, experimental systems have gained in complexity and emphasized the cooperation of multiple potentially pathogenic pathways such as specific CD41 T-cell immunity, the cytokine IL-15, intestinal microbiota and barrier function, and activation of transglutaminase 2 (a target of celiac disease-specific IgA autoantibodies) to break tolerance. Thus, despite some proof-of-principle demonstrations, the successful modeling of celiac disease in mice remains an outstanding challenge (Korneychuk et al., 2015).
Pernicious Anemia Pernicious anemia, the end-stage of autoimmune gastritis, presents an unusual case in the spectrum of autoimmune disorders: it is one of the most common and previously fatal autoimmune diseases, yet a highly effective
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treatment (vitamin B12 replacement) based in part on pioneering canine studies (Whipple et al., 1920) became available before a detailed understanding of the pathogenic mechanisms could be developed. From the 1980s onward, murine models of experimental autoimmune gastritis contributed to the generation of pertinent insights by exploring spontaneous and lymphopenia-induced disease courses, immunization with gastric H1/K1 ATPase, the use of infectious agents, and transgenic approaches (TCRtg T cells or GM-CSF expression by parietal cells). Notably, and in apparent contrast to many other autoimmune diseases, these models are considered to be particularly reliable and robust since they share key features with the human disease including H1/K1 ATPase as the major autoantigen targeted by both antibodies and T cells (Field et al., 2005; Toh et al., 2012). Perhaps as an unintended consequence of this unusually favorable constellation of therapeutic efficacy in the human disease, access to excellent in vivo models and an overall compelling grasp of major pathogenetic mechanisms, the current literature on pernicious anemia animal models is limited to but a few review articles and book chapters (van Driel et al., 2014). Nevertheless, we emphasize that the precise nature of disease initiating events remains little understood and that vitamin B12 therapy does not tackle the underlying cause of the disease which is associated with an increased risk for gastric cancer; further research and an exploration of additional treatment strategies are therefore warranted.
Ulcerative Colitis and Crohn’s Disease An impressive spectrum of IBD models established and/or refined over the past two decades has elucidated fundamental principles of human IBD pathogenesis including the unique tissue-specific constraints that drive intestinal inflammation through a complex interplay of microbiota, disrupted epithelial barriers, and dysregulated immune responses (in particular polarized T helper and innate immunity) (Jamwal and Kumar, 2017). In a recent authoritative review, Kiesler et al. (2015) have organized IBD models into five major groups comprising dextran sulfate sodium colitis, TNBS (trinitrobenzene sulfonic acid) colitis, oxazolone colitis, adoptive cell transfer-induced colitis, and IL-10-deficient mice. Informed by the notion that no single model captures the complexities of human IBD, relevant insights can nevertheless be generated as composite constructs that draw on the strength of individual models to illuminate particular aspects of specific diseases. Thus, instead of emphasizing the lack or shortcomings of mouse models for ulcerative colitis (UC) or CD, this model- rather than diseasecentered conception advocates for a deliberately distributed approach to disease study that builds on the specific contribution of multiple models to progressively reconstruct human IBD entities (Kiesler et al., 2015). Obviously, the particular extent to which individual models prove useful in this context can vary considerably. For example, oxazolone colitis is considered a useful “UC model” on the basis of morphological and immunopathogenetic aspects shared with the human disease; at the same time, IL-10-deficient mice may highlight other aspects of UC development since polymorphisms at the IL-10 locus confer increased disease risk in humans. IL-10 polymorphisms or IL-10R mutations are also associated with an enhanced CD risk or a familial form of early onset CD, respectively, demonstrating the utility of IL-10-deficient mice in CD research. Adoptive transfer colitis and especially TNBS colitis models further reproduce important features of CD but an integrated “CD model” has not yet been established. Lastly, we note that the experimental modeling of IBD pathogenesis goes well beyond the major (and minor) mouse models mentioned here and ranges from invertebrates (nematodes, insects, fish) to other rodents (rats, guinea pigs) and related species (rabbits) as well as pigs, ruminants, dogs, and nonhuman primates (Jiminez et al., 2015).
Autoimmune Hepatitis Attempts to establish animal models of AIH, beyond a few scattered earlier reports, slowly gained traction from the 1960s onward with an almost exclusive focus on immunization with liver antigens in adjuvant (Lohse and Meyer zum Bu¨schenfelde, 1994). Since the early 1990s, more than two dozen murine AIH models were introduced and include protocols for immunization with surrogate antigens; transgenic antigen expression, use of TCRtg T cells, or a combination thereof; certain systemic or conditional immunodeficiencies; dendritic cell immunization; viral infection; and challenge with AIH type-2 antigens (CYP2D6: 2D6 isoform of the large cytochrome P450 enzyme family; FTCD: formiminotransferase cyclodeaminase). These models have been reviewed in great detail (Christen and Hintermann, 2015, 2016; Czaja, 2010; Hardtke-Wolenski et al., 2012; Yuksel et al., 2014) and collectively support the sobering conclusion that truly satisfactory and reliable mouse models reflecting the clinical and histopathological features of human AIH have not yet been developed. In the majority of models, an
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acute breakdown of tolerance to liver antigens is readily achieved but cannot be maintained due to the inherent tolerogenic capacity of the liver and the relative efficacy of immunoregulatory mechanisms. Immunization with adenoviral vectors expressing CYP2D6 or FTCD shows promise based on its capacity to promote the development of chronic hepatitis and fibrosis, and these models can conceivably be improved through a concurrent inhibition of peripheral tolerance pathways. However, these experimental strategies are restricted to the modeling of type-2 AIH and mouse models specific for the Bsixfold more frequent type-1 AIH have not yet been established (though the targeting of PD-1, Tim-3, and/or IL-4R pathways is being considered).
Primary Biliary Cirrhosis Apart from reports on an age-associated development of PBC-like liver lesions in C57BL/6 mice some 25 years ago, PBC appeared somewhat resistant to the study in suitable small animal models. However, over the past 15 years, about a dozen murine PBC models have been reported that feature both spontaneous and induced development of disease (Concepcion and Medina, 2015; Katsumi et al., 2015; Leung et al., 2012; Pollheimer and Fickert, 2015; Wang et al., 2014). The former models employ congenic mice including spontaneously occurring mutations (scurfy, MRL/lpr) and genetic modification such as IL-2Ra deficiency or T-cell-specific suppression of TGFβ signaling while the latter approach includes xenobiotic immunizations and bacterial infections. Several recent and comprehensive reviews offer a consensus assessment that the complex nature of PBC pathogenesis and pathology cannot be captured in a single animal model but may now be studied in complementary models that adequately recapitulate specific aspects of the disease (Concepcion and Medina, 2015; Katsumi et al., 2015; Leung et al., 2012; Pollheimer and Fickert, 2015; Wang et al., 2014).
Vitiligo Spontaneous vitiligo develops in horses carrying the dominant Gray allele (Arabians, Andalusians, and Lipizzaners), Sinclair miniature swine, certain dog breeds, water buffalo, and Smyth line chicken (Erf, 2010; Essien and Harris, 2014). Among these, the Smyth line chicken constitutes the most important vitiligo model since it recapitulates many aspects of the human condition and permits an integrated evaluation of genetic determinants, melanocyte defects, and autoimmune responses throughout all stages of the disease (Erf, 2010). In the absence of a spontaneous mouse model (the “vitiligo mouse” [mivit/mivit] does not reflect mechanisms operative in the human disease since disease develops independent of a functional immune system, and the underlying point mutation in the Mitf gene does not correspond to any mutation in human vitiligo), the induction of vitiligo in mice has been achieved through chemical sensitization, immunization with melanocyte antigens, and, perhaps most prominently, TCRtg CD41 and CD81 T-cell populations recognizing melanocyte or model antigens (Essien and Harris, 2014). As with other autoimmune disorders, the complexities of the human disease cannot be reproduced by a single animal model and necessitate a composite approach that takes into account specific strengths and weaknesses of individual models.
Alopecia Arreata Similar to humans, adult onset alopecia areata (AA) can be observed in dogs, horses, cattle, and nonhuman primates but these animals typically do not serve as experimental disease models (Sundberg et al., 2015). The first reported animal model for AA was the “Dundee experimental balding rat,” and although it is no longer in use, it was instrumental in demonstrating that AA is a T-cell-mediated autoimmune disorder. Currently, the most prominent models are inbred C3H/HeJ mice that develop spontaneous or induced AA-like hair loss, and the xenotransplantation of healthy human scalp onto SCID mice followed by intracutaneous injection of IL-2activated human PBMC; the latter model is noteworthy for the fact that it effectively phenocopies a major autoimmune disease using previously healthy primary human tissue (Gilhar et al., 2016). Among other insights, the C3H/HeJ model confirmed a central role for IFNγ in AA pathogenesis and provided the proof-of-principle that Janus kinase inhibitors are suitable agents for AA management (Gilhar et al., 2016). Of potentially farther reaching importance is the notion that the considerable progress in preclinical AA research may establish AA as a “model disease” that offers both conceptual and practical tools for the study of less accessible organ-specific autoimmune diseases that share certain pathogenic determinants such as T1D and MS.
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Dermatitis Herpetiformis DH is an autoantibody-mediated autoimmune blistering disease caused by gluten consumption and may be considered a skin manifestation of celiac disease. Accordingly, the challenges pertaining to the establishment of a robust celiac disease model also apply to DH. To date, the first and only DH model that captures some of the genetic and clinical features of the human disease is a transgenic NOD mouse expressing HLA-DQ8 instead of murine MHC-II, and similar treatment responses in humans and HLA-DQ8 transgenic NOD mice further underscore their experimental utility for exploration of pathogenic mechanisms and novel therapeutic modalities (Marietta and Murray, 2012; Marietta et al., 2012; Pollmann and Eming, 2017). While it is not unreasonable to predict a refinement and diversification of DH models in the future, we also note that no new models have been reported since the original introduction of the HLA-DQ8 NOD mouse a dozen years ago.
Multiple Sclerosis With no other animal species developing a spontaneous demyelinating disease of sufficient similarity, MS appears to be an autoimmune disorder unique to humans (Ransohoff, 2012). This, however, has not hampered the creation of multiple animal models that are typically grouped into the three main categories of experimental autoimmune encephalomyelitis (EAE), virus-induced chronic demyelinating disease, and toxin-induced demyelination. Collectively, these models have established and illuminated various pathogenetic, clinical, and therapeutic correlates of the decidedly heterogeneous human disease, and numerous review articles have discussed in exquisite detail their roles in past, present, and potentially future investigations, their principal prospects and apparent limitations, and their translational relevance or lack thereof (Baker and Amor, 2015; Denic et al., 2011; Kipp et al., 2017; Mix et al., 2010; Procaccini et al., 2015; Stimmer et al., 2018). Perhaps more so than anything else, historical contingency has turned EAE into one of the most prominent autoimmune disease models with some 10,000 articles on the topic currently featured in the PubMed database. The earliest evidence that encephalomyelitis could be triggered by challenging the immune system with “self-proteins” came from side effects associated with the use of Pasteur’s rabies vaccine at the end of the 19th century (Mackay, 2010). The vaccine, made from the dried spinal cord of rabies-infected rabbits, in some cases led to ascending paralysis. This postvaccination encephalomyelitis was shown in the late 1920s to also occur in rabbits immunized with extracts of normal human spinal cord or sheep brain; paralysis in challenged monkeys was shown to correlate with defined histological lesions and demyelination in the 1930s; and more formal demonstrations that EAE could be provoked in animals via a short course of injections of normal brain combined with Freund’s adjuvant were provided in the 1940s. In time, EAE research converged from nonhuman primates and larger rodents toward mice and to some extent relinquished neuropathological and -behavioral complexity in favor of greater experimental flexibility and control, economic feasibility, and important ethical considerations that limit the use of higher species in animal research. Altogether, EAE research has proved fruitful for the identification of immunological and genetic determinants of disease pathogenesis as well as the study of histopathological features but decidedly less so for an evaluation of new treatment modalities. Among the other classes of MS animal models, infection with Theiler’s murine encephalomyelitis virus constitutes a well-defined experimental system that has contributed important discoveries about the initiation and perpetuation of autoimmune processes, demyelination, and even behavioral alterations. Similarly, the mouse hepatitis virus system provides a controlled framework for a comprehensive analysis of specific immune responses at the interface of pathogen control and targeted immunopathology. Lastly, toxin-induced models, the most popular of which are feeding of the copper chelator cuprizone and the microinjection of lysophosphatidyl choline, are particularly useful for the study of remyelination and therefore have important translational potential (although they do not address the autoimmune nature of MS) (Baker and Amor, 2015; Denic et al., 2011; Kipp et al., 2017; Mix et al., 2010; Procaccini et al., 2015; Ransohoff, 2012; Stimmer et al., 2018). Beyond the applied specifics of EAE research in particular and MS models in general, two aspects are worth emphasizing: (1) basic experimental strategies originally established for EAE studies have come to serve, arguably for better and worse, as a general template for the development of many other organspecific “experimental autoimmune” models and (2) the long history and extraordinarily rich record of EAE experimentation offer an abundance of detailed and diversified insights that can and should inform important discussions about the utility, constraints, pitfalls, and future directions of animal studies in autoimmune disease research. It is certainly not a coincidence that the apparent limitations of animal research have been most readily identified and critically assessed in the very fields that benefitted from a profusion of published in vivo studies (i.e., MS and T1D research); the resultant recommendations, namely, a careful selection of particular animal
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models to address specific and only partial aspects of the human disease, may appear as a more modest goal but in fact emphasize the fundamentally dialogical nature of animal experimentation, that is, the necessity to better define human pathophysiology so as to better tailor the corresponding animal studies.
Narcolepsy Narcolepsy type 1 (NT1) arises from the presumed autoimmune-mediated destruction of hypocretin/orexinproducing neurons in the hypothalamus (NT2, despite many clinical similarities, is a poorly defined heterogeneous disorder of unknown origin). However, the evidence supporting an autoimmune pathogenesis for NT1 is at best indirect (autoreactive antibodies and T cells detected only in some cases in blood but not hypothalamus) and circumstantial (association with certain HLA haplotypes, likely role of environmental triggers) (Kornum et al., 2017). Narcolepsy has been observed in several animal species (cat, horse, sheep, and cattle), and familial canine forms of the disease, established in the 1970s as a model system, were instrumental for the identification of orexin 2 receptor mutations as an underlying gene defect in 1999. At the same time, a narcolepsy phenotype was described in hypocretin-deficient mice, and since then, multiple genetically engineered strains have been generated including a model for inducible ablation of hypocretin neurons (Chen et al., 2009; Sakurai, 2015; Sinton, 2010; Toth and Bhargava, 2013). Among the attempts to create a mouse model that better mimics the potential autoimmune pathogenesis of NT1, a most recent approach demonstrated that mice expressing a “neoself-antigen” specifically in hypocretin neurons developed NT1-like symptoms after transfer of CD81 but not CD41 effector T cells specific for that antigen (Bernard-Valnet et al., 2016). However, despite the experimental utility of the NT1 models generated to date, their contributions to an elucidation of autoimmune processes operative in the human disease have been limited (Kornum et al., 2017).
Immune Thrombocytopenic Purpura Primary chronic immune thrombocytopenic purpura (ITP), resulting from the autoantibody-mediated targeting and destruction of platelets, is not limited to humans and has been reported for various domesticated animals such as dogs, cats, pigs, and horses; similarly, a remarkably broad range of animals (mice, rats, guinea pigs, rabbits, marmosets, swine, sheep, cattle, and horses) has served as recipients of heterologous anti-platelet serum in the so-called passive ITP model (Semple, 2010). However, out of practical, economic, and ethical considerations, ITP research has moved over the past 20 years toward mice as the primary model (Neschadim and Branch, 2015). In addition to the popular passive transfer model nowadays mostly employing monoclonal anti-platelet antibodies, “secondary ITP” models encompass various experimental scenarios wherein ITP emerges as a consequence of an underlying disease (e.g., “spontaneous” ITP in the [NZWxBXSB]F1 lupus mouse), drug therapy, infection or immunization, and “platelet-induced” ITP models make use of platelet GP-deficient mice and/or adoptive transfer of sensitized T cells. The development of a convincing humanized ITP mouse model, however, has apparently not yet been achieved (Neschadim and Branch, 2015; Semple, 2010). Overall, the available ITP models have served quite well in reproducing critical features of the human disease and therefore will continue to inform investigations into pathogenic determinants and novel treatment options.
Giant Cell Arteritis The estimated prevalence of giant cell arteritis (GCA), also known as temporal arteritis, seems to be on par with that of UC or CD; yet in contrast to the considerable investment into the development of animal models for IBD, in vivo studies of GCA appear to be limited to a single experimental strategy introduced some 20 years ago. Originally conceived by Weyand et al. (Brack et al., 1997a,b), temporal artery SCID mouse chimeras (NOD SCID mice subcutaneously engrafted with temporal artery specimens obtained from GCA patients) have been used in about a dozen studies investigating aspects of disease pathogenesis and/or therapeutic modalities (Weyand and Goronzy, 2013). An explanation for the lack of other GCA models certainly has to consider diseasespecific constraints and challenges in developing suitable rodent models but contributing factors are probably the advanced age of the patient population and the overall excellent response to high dose corticosteroid treatment (Frohman et al., 2016).
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CONCLUSIONS Building largely on the established concepts and hypotheses but facilitated and accelerated by remarkable technological advances, many new, refined, and improved animal models for organ-specific autoimmune diseases have been introduced in the early 21st century. Altogether, they have considerably contributed to our understanding of fundamental immunological processes in health and autoimmune disease yet the degree to which they have precipitated therapeutic progress is less clear. The reasons for this shortcoming are undoubtedly manifold, but we contend that it is above all a relative “lack of diversity” that has compromised the reproducibility, robustness, and relevance of preclinical animal studies. (1) Reproducibility: several recent publications reexamining successful strategies for T1D prevention and/or reversion in the NOD model have failed to replicate previously published results (Gill et al., 2016; Grant et al., 2013; Pham et al., 2016) and thus are symptoms for the more pervasive “reproducibility crisis” afflicting animal studies in diabetes research (Ackermann et al., 2018; van der Meulen et al., 2018) and beyond (Drucker, 2016). Confronting these challenges require nothing short of a recalibration of our research culture (Drucker, 2016; Flier, 2017) that in particular will have to incentivize independent verification of potentially significant observations by implementation of applicable experimental protocols under deliberately varied conditions (other research teams, facilities, locations, etc.). (2) Robustness: specific inbred and genetically defined mouse strains evaluated under strictly controlled environmental conditions not only offer unique research opportunities but also impose considerable constraints that limit any generalization of experimental findings to outbred populations; the deliberate diversification and extension of investigations to other strains as well as “wild” (outbred) and “dirty” (subjected to natural environmental exposures including pathogens) mice may lend much needed robustness to consequential conclusions (Abolins et al., 2017; Masopust et al., 2017; Sellers et al., 2012; Tao and Reese, 2017). (3) Relevance: while it is generally agreed upon that no single autoimmune disease model captures all relevant aspects of the human disorder, principal limitations observed in particular for murine models need to be considered more carefully (Davis, 2008; Mestas and Hughes, 2004; Zschaler et al., 2014); the translational potential of animal studies therefore increases with the degree to which experimental findings are supported by a mosaic of carefully chosen, complementary, and diversified model systems. Lastly, we need to consider the possibility that animal models may at times hamper rather than promote progress. For example, in their excellent 2007 review of mouse models for psoriasis, Gudjonsson et al. (2007) issue the lament that “lack of a suitable animal model has greatly hindered research into the pathogenesis of psoriasis”); Guttman-Yassky and Krueger (2007) on the other hand argue in a contemporaneous article that animal models may sometimes “hinder the overall translational enterprise” that, in the case of psoriasis, has brought about “rapid advances in pathogenic understanding and development of new therapeutics”. The notion that animal models can distort our perspective onto the human disease is also echoed by most recent histopathological findings in human T1D that challenge some of the central tenets about T1D pathogenesis as established in rodent models (Battaglia and Atkinson, 2015). The potential dangers of narrowing our investigative scope along the dictates of the “murine-industrial complex” are further elaborated and vividly illustrated in a journalistic essay aptly entitled “The Mouse Trap” (Engber, 2011). The specific utility, value, and importance of animal research arise only in a larger context of biomedical knowledge formation that draws on extraordinarily wideranging ideas, disciplines, tools, and practices and that integrates the specific contributions of animal models in an essentially cumulative and dialectical (or perhaps better dialogical) fashion (Carbone, 2012). The study of T1D and MS animal models in particular has generated an impressive wealth of data, information, and knowledge that also has illuminated the very limitations of this type of research endeavor (Wekerle et al., 2012). Moving forward from this point can neither mean “business as usual” nor a radical break with the past but perhaps a strategic “retreat from the seductions of model organisms to something more diverse—a throwback, perhaps, to the slower, more comparative style of the 19th century, when theories were constructed from the differences among the many, rather than the similarities of the few” (Engber, 2011).
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