In the last decades there has been a parallel increase in the incidence of food allergies and the development of experimental mouse models. These models have improved our understanding of the disease but do have limitations. For instance, they do not entirely reproduce human pathophysiology; moreover, validated and predictive models are absent. Nevertheless, the models provide opportunities to further understand fundamental disease mechanisms. The selection of any of the many experimental models depends on the research aims. This overview focuses on IgE-mediated food allergy in wild-type, genetically modified, and humanized mouse models and presents a comprehensive overview of the currently used protocols, challenges, and limitations, as well as provides guidelines for model selection based on the three critical areas of research: 1) safety assessment, 2) evaluating treatment, and 3) elucidating pathophysiology. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.

List of Abbreviations

Allergies to food proteins are abnormal immunologic responses following the ingestion of food that leads to adverse reactions in susceptible individuals (Yu, Freeland, & Nadeau, 2016b). It is predominantly a disease of industrialized regions, with over 220 million people worldwide suffering from food allergies (Berin & Sampson, 2013; Dunlop & Keet, 2018; Jones & Burks, 2017; Sicherer, 2011; Sicherer & Sampson, 2018). In the last 20 years, the prevalence increased in the USA by about 18% (Branum & Lukacs, 2009; Gupta et al., 2012). The current incidence is approximately 6 to 8% of young children and 3 to 4% of adults, and the estimated prevalence is 4 to 8% for children and 10% for adults (Branum & Lukacs, 2009; Gupta et al., 2019).

The main food allergens are peanuts, tree nuts, milk, egg, soy, wheat, fish, shellfish, and sesame (Smeekens & Kulis, 2021). They cause a range of mild to life-threatening symptoms, including GI symptoms (e.g., tingling and itching of the mouth and throat, nausea, abdominal pain, vomiting, and diarrhea), hives (urticaria), swelling (angioedema) and redness (erythema), difficulty breathing, bronchospasm, and anaphylaxis. Because trace amounts of allergens elicit an allergic response, patients must avoid accidental exposure, which in turn reduces their quality of life (Mali & Jambure, 2012; Yu, Freeland, & Nadeau, 2016a).

Generally, food proteins are either ignored by the immune system or induce immune tolerance, which prevents allergies in most people. However, in susceptible individuals, food allergens can induce IgE-mediated, mixed IgE- and non-IgE-mediated, non-IgE-mediated, or cell-mediated immune responses (Spergel, 2006; Waserman & Watson, 2011; Waserman, Begin, & Watson, 2018). Th2 cells, B cells, allergen-specific IgE, basophils, and mast cells mediate the response to most food allergens (Lee, 2016). De novo sensitization to food allergens is thought to occur in the GI tract, airways, and/or skin, but the exact conditions remain unclear (Satitsuksanoa, Daanje, Akdis, Boyd, & van de Veen, 2021). Mechanistically, antigen-presenting cells and lymphocytes, upon allergen encounter, generate allergen-specific IgE antibodies, which crosslinks the FcR on mast cells and basophils, leading to degranulation and the release of histamine, leukotrienes, prostaglandins, and other immune mediators (Anvari, Miller, Yeh, & Davis, 2019; Michelet, Balbino, Guilleminault, & Reber, 2021; Vickery, Chin, & Burks, 2011). Non-IgE-mediated/T cell-mediated food allergies are less common than IgE-mediated disease (Molkhou, 2016; Zhang, Sicherer, Berin, & Agyemang, 2021). The underlying mechanism for non-IgE-mediated allergy involves the generation of food protein-specific T cells that induce the release of inflammatory mediators, which cause GI tract and skin inflammation, e.g., dietary-protein-induced enterocolitis, celiac disease, and dermatitis herpetiformis.

The main experimental avenues for food allergy research include in silico , in vitro , and in vivo models aimed at the further understanding of the nature of allergens (Hayes, Rougé, Barre, Herouet-Guicheney, & Roggen, 2015), food protein permeability, stability, transport through the GI tract (Cubells-Baeza et al., 2015), barrier disruption of the epithelium (Gavrovic-Jankulovic, 2015), digestion (Dupont, 2015), sensitization, adaptive and innate immunity (Hussain, Epstein, & Noti, 2015; Smit, Noti, & O'Mahony, 2015), IgE and non-IgE mechanisms (Lozano-Ojalvo, Lezmi, Cortes-Perez, & Adel-Patient, 2015), the influence of the microbiome and diet (Barcik, Untersmayr, Pali-Schöll, O'Mahony, & Frei, 2015), and the potential allergenicity of novel foods including GMOs (Marsteller, Bøgh, Goodman, & Epstein, 2015).

The dawn of animal models for the study of food allergy was in 1911 when Wells and Osbourne followed up on the original finding by Besredka that feeding guinea pigs protein induced oral tolerance (Besredka, 1909; Wells, 1911; Wells & Osborne, 1911). Several decades later, oral tolerance was induced to bovine serum albumin (Thomas & Parrott, 1974) and red sheep blood cells (André, Heremans, Vaerman, & Cambiaso, 1975) in rats and mice, respectively. By 1977, an OVA model was developed in mice which showed feeding OVA caused oral tolerance (Vaz, Maia, Hanson, & Lynch, 1977). Soon after, Elson and Ealding found that CT could break oral tolerance in mice (Elson & Ealding, 1984), thus, establishing the basis for food allergy models.

In the last three decades, models of oral tolerance shifted towards modeling food allergy to elucidate the roles of the route of sensitization, consumption dose, e.g., timing and duration, adjuvants, maternal-fetal allergen transfer, cross-reactivity, e.g., pollen–food allergy syndrome (Chong, Ruiz-Garcia, Patel, Boyle, & Turner, 2020; Wang, Hu, Liu, Liu, & Li, 2020), co-morbidity, e.g., atopic dermatitis (Lack, 2012; Ohsaki et al., 2018; Sbihi et al., 2019) and inhalant allergies, the influence of the intestinal microbiome, and for evaluating novel therapeutics (Kanagaratham, Sallis, & Fiebiger, 2018; Smeekens & Kulis, 2021).

Mice are the preferred choice for investigators because of their closely related immune and allergic responses to humans. Rats, like the Brown Norway strain, are also favored for food allergy because of high IgE responses (Ballegaard, Madsen, & Bøgh, 2019) and ease of serial serum antibody monitoring (Pilegaard & Madsen, 2004). Compared to rats, mice have shorter breeding times, lower maintenance costs, larger numbers of wild-type, KO, tg strains, and immunological reagents, as well as requiring a lower amount of test materials (Bøgh et al., 2016). However, mouse models do have their limitations: 1) they do not entirely reproduce human pathology, 2) there are no validated and predictive models, 3) the models that require added adjuvants might not be useful for investigating sensitization or oral tolerance, because its role in human disease is unknown, 4) mice rarely develop anaphylaxis with low amounts of oral food protein, in contrast to patients (Arumugam et al., 2011; Burton et al., 2017; Capobianco et al., 2008; Lexmond et al., 2017; Li et al., 2000; Smeekens et al., 2020; Tordesillas et al., 2014), especially because ingested antigens must be systemically absorbed to induce anaphylaxis in mice (Strait et al., 2011), 5) except for polysensitized WASP-deficient mice, they do not develop spontaneous disease, and 6) both anaphylactic IgG1 and IgE mediate anaphylaxis in mice, but not in humans (Smeekens & Kulis, 2021). There are many protocols for inducing disease in mice, each with inherent strengths and weaknesses.

This comprehensive overview focuses on IgE-mediated food allergies in wild-type, GM, and humanized mouse models from 2000 to 2022 and includes a brief overview of rat models. We present protocols that are currently in use, the challenges and limitations of the models, and guidelines for model selection based on three critical areas of research: 1) safety assessment, 2) evaluating treatment, and 3) elucidating pathophysiology.

Although food allergy in mice is similar to human food allergy, it is not identical (Kanagaratham et al., 2018; Smeekens & Kulis, 2021). Nevertheless, in vivo food allergy models are a facsimile of disease and have improved our understanding of disease (Oyoshi, Oettgen, Chatila, Geha, & Bryce, 2014). Fifty-nine representative food allergy models, including 32 wild-type, 20 GM, and 7 humanized mice models, are listed in Tables 1, 4, and 5.

Wild-Type Mouse Models

The majority of models use wild-type mice. Table 1 provides examples of wild-type mouse models and highlights the allergens, sensitizing, and eliciting routes of allergen administration, the use of adjuvants, and the mouse strain. Although BALB/c mice are most frequently used, other strains include B10.A (Tanaka et al., 2011), 129SvEvBrd (Arumugam et al., 2011), C57BL/6 (Brandt et al., 2003; Dolence et al., 2018), and C3H/HeJ (Li et al., 2000; Moutsoglou & Dreskin, 2016; Proust et al., 2008), and are primarily conventional mice, SPF and germ-free (Feehley et al., 2019) mice are also used. Wild-type mice do not appear to spontaneously develop food allergies like other animals, e.g., dogs and cats (Teuber et al., 2002). Therefore, it is necessary to sensitize them with protein. The proteins that have been commonly used are from food sources containing allergens, such as chicken egg white (e.g., OVA), cow's milk (e.g., BLG, whey), peanut (e.g., extract, Ara proteins), fruit (e.g., peach), legumes (e.g., lupin, peas, beans), and shellfish (e.g., shrimp tropomyosin). The allergenic proteins are administered as either whole food (most often as a suspension) (Burton et al., 2017; Lee et al., 2013; Smeekens & Kulis, 2021), purified proteins (Arumugam et al., 2011; Brandt et al., 2003; Burggraf et al., 2011; Capobianco et al., 2008; Hussain et al., 2018; Lam et al., 2015), or protein extracts (Dolence et al., 2018; Hardy et al., 2022; Li et al., 2000; Parvataneni, Gonipeta, Acharya, & Gangur, 2015; Smeekens & Kulis, 2021; Strid, Hourihane, Kimber, Callard, & Strobel, 2005; Tordesillas et al., 2014; Utsch, Logiantara, van Ree, & van Rijt, 2017).

There are two steps to induce allergy to food proteins or whole food: the first is to initiate an immune response to the protein in the animal, and the second is to elicit a secondary response. Sensitization induces allergic responses to one, or multiple, food proteins by administering proteins, extracts, or whole food by i.p., s.c., epicutaneous, transcutaneous, or i.g./p.o. routes. Once the animals are sensitized, the next step is the elicitation of an in vivo response, which is achieved by an allergen challenge administered by oral, dermal, systemic, or respiratory tract exposure. In some instances, sensitization and elicitation phases are induced with the same allergen, while in others, they may differ. For example, sensitizing with a purified protein and challenging with the whole food or vice versa (Burggraf et al., 2011; Lee et al., 2013; Li et al., 2000; Prescott et al., 2005; Proust et al., 2008).

A variety of adjuvants are used when administering purified proteins to reduce the risk of inducing oral tolerance (Mullins et al., 2022). Examples of adjuvants used in mouse models are CT, alum, and SEB (Ando et al., 2017; Arumugam et al., 2011; Brandt et al., 2003; Capobianco et al., 2008; Feehley et al., 2019; Lam et al., 2015; Moutsoglou & Dreskin, 2016; Rodriguez et al., 2012; Tanaka et al., 2011; Zhao et al., 2021; Zlotkowska et al., 2021), CpG oligonucleotide (Adel-Patient et al., 2007), LPS (Rodriguez et al., 2017), Freund's adjuvant (Zlotkowska et al., 2021), Calcipotriol (Hussain et al., 2018), and house dust mite extract or indoor dust (Dolence et al., 2018) but are usually unnecessary when immunizing with whole food.

The experimental in vivo endpoints for wild-type, GM, and humanized mouse models are similar (Castan et al., 2020) (Table 2). Briefly, in vivo readouts for food allergy include diarrhea, scratching, piloerection, and reduced activity. Clinical scores have been developed to assess clinical signs, e.g., (0) no symptoms; (1) scratching and rubbing around nose and head; (2) puffiness around eyes and mouth, diarrhea, pillar erect, reduced activity, and/or decreased activity with increased respiratory rate; (3) wheezing, labored respiration, and cyanosis around mouth and tail; (4) No activity after prodding, or tremor and convulsion; (5) death (Li et al., 2000).

Anaphylaxis is assessed by a drop in core body temperature upon allergen challenge. Vascular leakage, an indicator of anaphylaxis, is evaluated following i.v. injection of Evan's blue immediately after an allergen challenge and visualized by blue color in the extremities (Evans, Killoran, & Mitre, 2014). Vascular leakage can also be measured by passive cutaneous anaphylaxis following an immediate allergen response, assessed by ear thickness and skin color after i.v. injection of Evans blue (Evans et al., 2014). Other in vivo readouts for allergen sensitization include i.d. allergen challenge in the ear, leading to an ITH readout as ear swelling (van Esch et al., 2010). Alternatively, allergen administered s.c. in the ears or footpads can be evaluated by measuring ear thickness, which is indicative of a DTH response (Prescott, Forbes, Foster, Matthaei, & Hogan, 2006). Lastly, AHR following an allergen challenge in the respiratory tract is an indicator of sensitization (Prescott et al., 2005).

Ex vivo endpoints for food allergy are similar to most immunological assessments for immunization with antigen, (Table 3) but focus on Th2 immune responses. The most common readouts are allergen-specific IgE and IgG1 titers (Birmingham et al., 2003). Although serum allergen-specific immunoglobulins are detected, a significant issue is that the IgE might be biologically inactive. The IgE functional activity can be tested with the in vitro rat basophil activation assay, which evaluates the ability of serum IgE to induce basophil degranulation (Bøgh et al., 2009). Other readouts include determining cell phenotype, activation and function of innate and adaptive immune cells from the GI tract, blood, and lymphoid organs, measuring cytokines, e.g., IL-4, IL-5, IL-13, IL-25, and IL-33, etc., and mediators, e.g., mast cell proteases, histamine, and tryptase. Evaluating inflammation and edema in the intestine with histological methods is also valuable (Hogan, Mishra, Brandt, Foster, & Rothenberg, 2000; Li et al., 2000; Mathias et al., 2011; Utsch et al., 2017; Walker et al., 2018; Yamani et al., 2018). Gene expression profiling, transcriptomics, proteomics, microbiota analysis, and epigenomics might provide valuable markers for sensitization and lead to novel mechanistic insights. Additional approaches include organ culture models (Tsilingiri et al., 2012), organoids and intestinal organ culture systems (Clevers, 2016), and gut-on-a-chip (Kim, Li, Collins, & Ingber, 2016).

Genetically Modified Mouse Models

Transgenic and KO mice offer opportunities to derive novel mechanistic insights into the pathophysiology of food allergy. Table 4 presents examples of GM mouse models. Except for mice deficient in WASP that develop IgE-mediated reactions to food allergens (Lexmond et al., 2016), none of the previously used tg and KO mice spontaneously develop food allergies. The range of tg mice used in food allergy models include those expressing genes such as IL-4 (Hussain et al., 2018; Tomar et al., 2021), IL-4Rα (Burton et al., 2013; Ganesan, Sharma, Tomar, Schuler, & Hogan, 2022; Mathias et al., 2011; Tomar et al., 2021), IL-5 (Brandt et al., 2003), IL-9 (Ahrens et al., 2012; Ganesan et al., 2022; Yamani et al., 2021; Yamani et al., 2018), IL-13 (Tordesillas et al., 2014), IL-25 (Lee et al., 2016), GATA (Hussain et al., 2018), FcεRI (Ahrens et al., 2012; Brandt et al., 2003), human CD22 (Hardy et al., 2022), Baso-DTR (Noti et al., 2014), T cell receptor, e.g., DO11.10 (Tordesillas et al., 2014) and OT-II (Platzer et al., 2015), Abl1 (Yamani et al., 2018), TSLPR (Noti et al., 2014), filaggrin and Tmem79ma (Walker et al., 2018), CC027 (Smeekens & Kulis, 2021), WAS (Lexmond et al., 2016), Foxp3 (Lexmond et al., 2016), TGAX (Lexmond et al., 2016) combined with eGFP and assorted cell markers. Examples of KO mice used to study food allergy lack single or combinations of genes, including FcεRI (Brandt et al., 2003), FcRI-chain (Sun et al., 2007), IL-4 (Lexmond et al., 2017), IL-5 (Hogan et al., 2000), IL-17rb (Lee et al., 2016), eotaxin (Hogan et al., 2000), IgE, TSLP, and Igh7 (Noti et al., 2014), CD40L (Sun et al., 2007), Rag2 (Lexmond et al., 2016; Lexmond et al., 2017), and mice that lack B cells and mast cells (Sun et al., 2007). The food allergens used in the GM mouse models are similar to those used in wild-type models, e.g., related to milk, OVA, peanut, tree nuts, legumes, and fish, and used with and without adjuvants. The sensitizing and eliciting approaches are also similar to those used in wild-type mice, except for models using adoptive cell transfers with tg T cell receptor-expressing T cells from the DO11.10 and OT-II tg mice (Hussain et al., 2018; Platzer et al., 2015; Tordesillas et al., 2014).

Humanized Mouse Models

Humanized mouse models generated by engrafting human cells or tissues into immunodeficient mice (Walsh et al., 2017) are predominantly created by injecting human PBMCs or HSCs from healthy or allergic donors into SCID mice (Burton et al., 2018; Burton et al., 2017; Hardy et al., 2022; Parvataneni et al., 2015; Wang et al., 2022; Weigmann et al., 2012) (Table 5). The SCID mice lack B and T cells and, in some cases, have been crossed with tg and KO mice (Ito et al., 2021). The advantage of humanized mice is that they provide an opportunity to study an in vivo human immune system. However, there are limitations with these mice, including potential problems with the initial engraftment, graft-versus-host disease, and challenges related to distinct species-specific molecular, cellular, and organs that could alter the resulting pathophysiology. Additionally, humanized mice engrafted with an allergic donor cannot be used to evaluate sensitization because the T cells are already primed (Parvataneni et al., 2015; Wang et al., 2020; Weigmann et al., 2012). In contrast, elicitation can be assessed using various routes of allergen administration. It is also possible to elicit passive anaphylaxis with an injection of an i.v. antibody (Burton et al., 2018). In mice derived from non-allergic donors, sensitization has been done by i.p., i.g., and i.n. allergen administration with food proteins, including peanuts (Parvataneni et al., 2015; Wang et al., 2020), tree nuts (Weigmann et al., 2012), pollen (Weigmann et al., 2012), and house dust mite (Wang et al., 2020). Typically, adjuvants are not used in these models.

Rat Models

Food allergy is induced in the rat by epicutaneous, p.o., and i.g. administration of protein. Examples in Table 6 are in the Brown Norway rat with gluten and OVA allergens. Skin sensitization requires weekly abrasions before administering the protein samples without adjuvant (Ballegaard et al., 2019). The elicitation is done by i.p., i.g., i.d., or p.o. allergen exposure. The readouts are similar to those used in mouse models.

There are many challenges with food allergy models that could limit the experimental outcomes. These challenges can significantly influence model reproducibility as well as the translation to human disease. Designing a food allergy model is especially challenging because careful attention must be paid to the types of allergens and controls, the type and characteristics of the mice, e.g., age, gender, and strain, and the conditions for allergen exposure, including the use of adjuvants, environmental conditions, intestinal microbiome, and diet, which can influence the results.

Allergens

A significant challenge in food allergy model design is the selection of test allergens. Most investigators use known allergenic proteins and foods to ensure that the model reflects human allergy. Although there are few allergenic food proteins in humans (Bannon, 2004), most proteins, even non-allergenic ones, will induce an immune response in wild-type mice (Ladics et al., 2010). To date, there are no reports of non-allergenic food proteins in mice. However, a multi-laboratory study tested four wild-type mouse strains and clinically relevant allergenic proteins from peanut and cow's milk and non-allergenic proteins with a history of safe use in humans from spinach and soybean i.p., with or without adjuvant (Ladics et al., 2010; Thomas et al., 2005). They found that known allergens induced higher responses compared with the low immunogenic spinach rubisco and soy lipoxygenase (Ladics et al., 2010; Thomas et al., 2005). The lack of non-allergenic proteins in mice means that there are only naïve and vehicle-alone negative controls. Ideally, a clinically relevant reference set of proteins with known allergenic potency would be useful, but it is unclear whether establishing reference proteins is feasible. Another factor that might affect the test materials and the consequent experimental outcome is the source and preparation of the allergen, e.g., protein processing, isolation, and purification methods may differ. The selection of well-characterized allergen test materials is essential for model reproducibility.

Testing for Protein Allergenicity

While purified proteins and extracts can induce food allergy, it is ideal to establish food allergy models with whole food to fully understand sensitization to food proteins embedded within the food matrix. The proteins in whole food differ significantly from purified proteins because of possible changes in protein folding, exposure of hidden epitopes, protein content in the whole food, and other food components that could interact and alter allergenicity. For example, intrinsic adjuvants such as lipids, carbohydrates, and other proteins could augment the allergic response (del Moral & Martinez-Naves, 2017). The food matrix might also alter protein digestibility and bioavailability, or contain protease inhibitors and additives (Keshavarz, Jiang, Hsieh, & Rao, 2019; Schulten, Lauer, Scheurer, Thalhammer, & Bohle, 2011). The choice of whole food, and the processing used, is crucial because, for example, the proteins in cooked and raw foods also differ. The best approach is to use the food as it would be prepared for human consumption, i.e., baked, boiled, microwaved, etc. Industrial food processing methods like high heat, hydrolysis, defatting, and pH changes might also influence allergenicity (Bøgh et al., 2016). Purified proteins also have associated challenges compared to proteins in whole food, such as the possibility of different folding, post-translational modifications, and endotoxin contamination of recombinant proteins.

The type of allergen is important for inducing allergy, but the amount necessary for sensitization also varies. Some proteins at high oral doses might induce oral tolerance (Burggraf et al., 2011; Mathias et al., 2011; Strid et al., 2005; Walker et al., 2018). Allergen dose, frequency of administration, and exposure route might alter the responses (Wavrin, Bernard, Wal, & Adel-Patient, 2015). Therefore, when using a novel allergen for sensitization, it is essential to establish a dose-response curve.

Adjuvants

Often adjuvants are used to induce disease by breaking oral tolerance, though some adjuvant-free models have been reported (see Tables 1, 4, and 5). Adjuvants are mainly used when administering purified proteins and extracts compared to a whole food, which may have intrinsic adjuvants. A model without adjuvant is preferable because they tend to skew immune responses (Bøgh et al., 2016), but all models using OVA, for example, in Table 1 add adjuvant. Using adjuvants for sensitization depends upon the experimental aim and should be considered when the focus is not on sensitization.

Exposure

The sensitizing and eliciting exposure approaches are vastly different between models (see Tables 1, 4, and 5). Sensitization may occur by systemic and local immunization. I.p., i.d., and i.n. induction of a systemic immune response sensitizes the mice for GI tract challenges. It is also possible to generate disease with oral challenges, which tend to induce local GI tract and systemic responses. The challenges or elicitation of food allergy following sensitization depend on the desired readout and research aim. Oral challenges are preferred when inducing GI tract inflammation (Mathias et al., 2011). In contrast, i.p. challenges lead to anaphylactic reactions, mast cell responses, vascular permeability (Sun et al., 2007), and T cell proliferation (Rodriguez et al., 2017). Challenges in the skin for a DTH response (Prescott et al., 2005) or i.n. for a respiratory response (Sun et al., 2007; Wang et al., 2020) provide evidence of initial sensitization in another organ system.

Because oral challenges are probably the major sensitizing route in humans, oral challenges would be the most translatable route of exposure. The protocols in use have a wide range of doses and frequency of oral challenges that could be days to weeks (Fig. 1). Ideally, the quantity and frequency of oral test material exposure should be based on human consumption.

Environmental Factors

Many other factors are essential for establishing a reliable and reproducible model of food allergy, including environmental factors, e.g., housing conditions, light cycles, temperature, humidity, noise level, and gentle handling of the mice to reduce stress. The environment should be as consistent as possible. Even factors like changes in bedding and enrichments could potentially skew the results. Experienced personnel should conduct repeated allergen administrations to ensure consistency. Attention should also be given to the potential for contaminated test materials, e.g., mycotoxins and endotoxin, and to a consistent intestinal microbiome, e.g., the mice should be bred in-house or come from the same vendor and fed the same diet, etc.

Mouse Age, Gender, and Strain

The age and gender of the experimental mice should be consistent because responses in newborn mice differ significantly from older, e.g., 6–8-week-old mice, though there is some evidence that animals older than 8 weeks respond similarly (Akiyama et al., 2001; Pilegaard & Madsen, 2004). The gender should also be consistent because food allergy in female mice and rats appears more robust than in males (Parvataneni, Birmingham, Gonipeta, & Gangur, 2009; Pilegaard & Madsen, 2004). The mouse strain, i.e., genetic predisposition, can influence the type of immune response. Using mice from the same vendor or bred in the same facility reduces variability, like in other models used for studying immunity. The use of germ-free mice helps avoid issues relating to the intestinal microbiome but this is dependent upon the research aim.

Diet

The diet should be consistent for inter- and intra-experimental comparisons. The same feed should be used for the animals during an experiment and in parental generations before mating or weaning. The same food with the same nutritional ingredients should be used. A balanced diet is essential as deficiencies, like vitamin A or D deficiency, might influence the results (Matsui et al., 2018). Changes in fat consumption might alter the intestinal microbiome (Hussain et al., 2019), and cross-reactive proteins in the feed (Lee et al., 2013) could influence the development of food allergy and the reproducibility of the model. In some experiments, optimal allergen absorption is promoted by fasting the mice for a few hours before oral challenges (Brandt et al., 2003; Li et al., 2000; Pagovich et al., 2016; Wang et al., 2020).

Translation

Most food allergy models are isomorphic, which means that symptoms/clinical signs and treatments are shared. Ideally, food allergy models should meet the following criteria to be translational: 1) the mice should have similar biology and clinical signs as humans, 2) the mice should react similarly to non-allergenic and allergenic proteins (or a low to high range of protein allergenicity) as humans, and 3) the mice should have the same pathophysiological responses as humans. To date, none of the models exactly reproduce disease. Nevertheless, similarities exist between disease in mice and humans, creating promising prospects for further elucidation of the factors governing food allergy.

The biology underlying allergic disease in mice and humans is similar. In atopic dermatitis and allergic asthma, a similar array of genes is expressed in mice and humans (Ando et al., 2013; Yu et al., 2011), and a large number of additional pathophysiological similarities exist (Oyoshi et al., 2014).

Food proteins with a history of safe use in humans, i.e., non-allergenic, can be allergenic in mice (Ladics et al., 2010). Furthermore, they have similar biology, but the clinical signs might differ. For instance, after consuming peanuts, the most severe peanut allergy patients could have life-threatening anaphylaxis upon trace amounts of the allergen (Hourihane et al., 1997; Taylor et al., 2002). Inducing anaphylaxis with small amounts of allergen administered p.o. has not been reproduced in mice.

Although allergen sensitization in mice leads to allergen-specific IgG1 and IgE and other ex vivo readouts (Table 3), it might not mimic the initiation of food allergy in patients. The use of allergen co-administered with adjuvants to sensitize the mice differs from patients, though there are likely intrinsic adjuvants in food like endotoxins, etc. (Schwarzer et al., 2017). It is unlikely that patients would encounter purified proteins, except for in vaccines, and there may be an association between OVA-containing vaccines and an increased risk of egg allergy (Kiraly et al., 2016).

Many individuals have food protein-specific IgE without food allergies (Anvari et al., 2019; Hamilton & Oppenheimer, 2015). Thus, food protein-specific IgG1 and IgE titers indicate that sensitization might not lead to food allergy. The allergen needed to elicit clinical signs in sensitized mice might differ significantly in the amount, frequency, timing, and route of the allergen challenge compared with patients. The main challenge is our understanding of 1) when and how allergen-specific IgE sensitization occurs in patients and 2) what kind of challenge elicits the onset of clinical manifestations.

Wild-type mice likely do not spontaneously develop food allergies like humans or companion pets (Bryan & Frank, 2010; Gaschen & Merchant, 2011; Olivry & Mueller, 2017). Although spontaneous food allergy models have been defined as those induced without exogenous adjuvant (Kanagaratham et al., 2018), sensitization and elicitation might not be similar enough to patients, mainly because the exact conditions needed to establish disease in humans are unknown. However, the WASP-deficient mice might provide an opportunity to understand spontaneous sensitization further as they are the only mice that become polysensitized to food proteins (Lexmond et al., 2017).

Although many models are listed in Tables 1, 4, and 5, their differences could be minimal. For example, the model might be the same, except that the timing of allergen administration differs. Table 7 highlights examples of protocols in use in wild-type mice as the most commonly used experimental animals and divides them into the following four categories based on allergen delivery: 1) oral sensitization and challenge, 2) oral sensitization and non-oral challenge, 3) non-oral sensitization and oral challenge, and 4) non-oral sensitization and non-oral challenge, with food proteins.

In category 1, six model protocols are shown that use p.o. administration routes for sensitization and elicitation. One protocol uses whole food for sensitization and elicitation, and others use protein and adjuvant to sensitize and protein with adjuvant, or protein alone, for challenges. These models aim to evaluate the immune responses, anaphylaxis, and GI tract effects.

In category 2, six models utilize oral sensitization followed by non-oral challenges via the respiratory tract, skin, or systemic (i.p.) to test for sensitization, i.e., to determine whether feeding whole food elicits immune responses. The readouts are in the skin, lungs, and in some cases, anaphylaxis.

Category 3 includes the most popular models. They are achieved by sensitizing the mice via the skin and followed by oral challenges. Most of these protocols use protein and adjuvant for sensitization, and protein for the oral challenge, though whole food is also used. These experiments aim to investigate the immune response to specific food allergens (including anaphylaxis in some) and their effect on the GI tract.

In category 4, three models sensitize via the lung with protein or whole food, and challenge systemically (i.p.). These models aim to study the allergenicity of food proteins.

Figure 1 provides an overview of twenty main types of protocols in a scheme that emphasizes the differences between the experimental designs. The protocols are clustered into the four categories above based on the route of allergen administration. The scheme illustrates the duration of the experiments runs from 2 to 10 weeks, and the number of times the allergen is administered, ranging from a total of 2 to 25 doses.

While it is tempting to argue that only protocols using oral sensitization and/or oral challenge are true food allergy models, this might be incorrect because the mechanisms underlying sensitization to food allergens remain elusive. For instance, there is growing evidence suggesting that food allergy may develop after non-oral sensitization routes, e.g., proteins found in topical agents, soaps, and cosmetics have been associated with food allergy (Codreanu, Morisset, Cordebar, Kanny, & Moneret-Vautrin, 2006; Fukutomi, Taniguchi, Nakamura, & Akiyama, 2014; Pootongkam & Nedorost, 2013) and the oral allergy syndrome is caused by cross-reactivity of food allergens with inhaled allergens like pollen (Popescu, 2015).

There is a wide selection of models with distinct protocols (Table 7, Fig. 1) that makes model selection challenging. However, the choice of model(s) should be fit-for-purpose and address research aims and hypotheses for either 1) safety for an allergenicity risk assessment, 2) evaluation of novel therapeutic strategies, or 3) pathophysiology to acquire new insights into pathophysiology and new therapeutic targets.

Safety or Risk Assessment for Allergenicity

A safety or allergenicity risk assessment of food proteins is crucial for protecting the public from de novo sensitization to novel foods before entering the market. Several approaches are used for predicting the allergenicity of novel proteins, which are mainly based on the Codex Alimentarius (Codex Alimentarius Commission, 2003-2009) and (reviewed in (Mullins et al., 2022)). In vivo models for a safety assessment should ideally be robust, reliable, reproducible, and standardized. A safety allergenicity risk assessment has been used for predicting the allergenicity of the newly expressed proteins in GMOs (Marsteller et al., 2015) but has yet to be validated. For allergenicity testing, the models could be potentially done in wild-type and appropriate humanized mice. It is ideal to compare whole food and protein extracts to purified protein, even though the use of whole food is complex and difficult. Processed food might also be important for testing because of the potential for increasing or decreasing protein allergenicity. The dosing, timing, and frequency of the test materials should be close to what is expected for human consumption. Oral administration is better because GI tract digestion could play a key role in sensitization to food allergens within a whole food. Considerations about dosing are important because of the possibility of inducing oral tolerance. Establishing a dose-response curve would be essential for these models. Adjuvant-free models are preferable.

Using safety and risk assessment models could be practical for assessing potential cross-reactivity with other food proteins. Two examples illustrate the importance of using whole food, and one study showed that the bean alpha-amylase inhibitor protein used to produce GM peas cross-reacted with the intrinsic pea lectin protein in peas (Lee et al., 2013), and the other demonstrated cross-reactive proteins in soybean and cow's milk (Smaldini et al., 2012). An in vivo model has also been used for assessing whether newly expressed proteins in GMOs might be adjuvants (Andreassen et al., 2016; Guimaraes et al., 2008; Lee et al., 2013; Prescott et al., 2005; Reiner, Lee, Dekan, & Epstein, 2014; Tulinska et al., 2018; Vazquez-Padron, Moreno-Fierros, Neri-Bazan, de la Riva, & Lopez-Revilla, 1999), though none have convincingly shown an adjuvant effect.

Objective and reproducible readouts are essential for an allergenicity risk assessment. The currently used readouts seem appropriate and are mainly allergen-specific IgE and IgG1, basophil activation test, and clinical signs of anaphylaxis, e.g., reduced temperature and mobility, diarrhea, gut inflammation, and other possibilities might include intestinal permeability.

Treatment Efficacy

Wild-type and humanized mouse models could be used to evaluate the efficacy and effectiveness of treatment for food allergy (Leonard, Martos, Wang, Nowak-Wegrzyn, & Berin, 2012; Yamaki & Yoshino, 2012). The models can vary widely with the type of allergen, adjuvant, and routes of administration that reproducibly sensitizes the mice and can elicit an allergic response. If an allergen-specific therapy is intended, then the sensitizing allergen should be the same as the targeted treatment. While evaluating treatment effectiveness in the elicitation phase is important, prophylactic approaches can be tested before and during sensitization, e.g., inhibition of sensitization of oral tolerance. The treatment models should have objective and reproducible readouts, similar to the safety models above.

Pathophysiology and Disease Mechanisms

The selection of mouse models focused on pathophysiology is the most challenging because they are the most varied and depend on the type of research hypotheses and questions being addressed. The models could be established with wild-type, GM, and/or humanized mice, and any of the allergens, adjuvants, and routes of allergen administration. The readouts include the main disease parameters used for the other models, but also extend to cellular phenotype and function, gene expression profiling, transcriptomics, epigenetics, etc. Tg and KO mice provide opportunities for these experiments to elucidate the molecular and cellular mechanisms influencing sensitization and elicitation by addressing the existing challenges with the models and providing a system in which to directly interrogate the hypotheses.

Model Selection Criteria

Food allergy from any protocol can be achieved as long as the mice are sensitized and challenged using any of the indicated mouse strains, allergens, with or without adjuvants, routes of administration, and environmental conditions (Tables 1, 4, 5, 7, Fig. 1). On the one hand, having so many options allows for ease in the selection of a model, because there are so many to choose from. On the other hand, model selection can be challenging because it is difficult to choose when there are so many options. Importantly, selecting a model protocol and endpoints should be based upon the research aims.

The decision-making process should begin with the choice of a model that is fit for the intended purpose, based on whether the research is aimed at studying the 1) allergenicity of a protein, 2) treatment effectiveness, or 3) pathophysiology (Table 8).

Based on the purpose of the model, the second step is choosing the allergen. Models using OVA are common because it is relatively inexpensive, has well-characterized immune responses and reagents, can cause oral tolerance and food allergy, is clinically relevant (egg allergy), requires adjuvant, and sensitization and elicitation can be done with purified protein as well as with whole food. Models with other relatively inexpensive allergens are whole food suspensions and extracts that are clinically relevant from peanuts and seafood. They can be done without adjuvants using a variety of allergen administration routes.

The third step is choosing the route of allergen administration and depends on whether the aim is to use whole food, which is best done by the p.o. route, or purified protein, which can be administered by any route and requires adjuvant. The choice between whole food and purified protein might be to mimic human consumption more closely, but it also depends on whether to focus on anaphylaxis or on GI tract inflammation, with or without anaphylaxis. Anaphylaxis is easier to elicit with purified protein.

The fourth step is choosing the mice. The most common strain is BALB/c, followed by C3H. There are strain differences, but not enough to warrant specifically using one over the other based on other criteria like type of allergen, route, etc. A tg or KO mouse strain might be ideal if the focus is on a particular gene or pathway. The choice to use humanized mice would also be possible depending on the aim being addressed.

The fifth step is selecting the models based on the research budget. For instance, the selection could be based on cost-effectiveness, e.g., a shorter model has lower mouse housing costs, requires less test material, and less labor. Other practical criteria might be the use of reagents available to the investigator, e.g., mouse strain, or GM mice, or a particular antigen.

The sixth step concerns investigator expertise and infrastructure. Establishing complex food allergy models would be facilitated by access to technology and facilities for creating tg, KO, and humanized mice and maintaining them in SPF and germ-free conditions. The selection of assays and readouts will depend upon the investigator's expertise and access to the needed instruments.

The wide variety of models provides a multitude of opportunities, but it is critical to base model selection on the hypothesis and research question. It is also possible that more than one model would be necessary. The selection of the best model(s) will become easier as our understanding of food allergy improves.

Translating basic lab results to patients with food allergies will require research leading to validated mouse models and a better understanding of the mechanisms underlying disease. A concerted effort integrating in silico , in vitro , and in vivo research findings will lead to discoveries and, ultimately, to clinical trials. Fundamental issues surrounding the disease in mice must address the development of translational models (Table 9).

Although experimental mouse models have limitations, they have a potential role in understanding mechanisms underlying food allergy, establishing safety from unknown effects of novel foods, as well as evaluating novel therapeutics. The selection of the model should be fit-for-purpose. Notably, using more than one model might be necessary to address a hypothesis fully.

Implementing any model requires careful attention to the experimental design and the factors influencing disease, including mouse strains, allergens, the use of adjuvants, routes, frequency and timing of allergen administration, and environmental conditions.

There are numerous unanswered questions about the pathophysiology underlying food allergy. These knowledge gaps require complementary research with other areas of allergenicity research, including in silico and in vitro models, to generate more information on the nature and properties of allergens, and the role of the GI tract, e.g., digestion, transport, protein permeability, and barrier disruption. Further research is necessary to fully understand de novo sensitization mechanisms to develop optimal, standardized food allergy models.

Sahar Kazemi : Data curation and writing-original draft; Ece Danisman : Data curation and writing-original draft; Michelle M. Epstein : Conceptualization, data curation, supervision, and writing-original draft.

The authors do not have financial or personal relationships between themselves and others that might bias the work. The support source was not involved in the protocol design and in the collection, analysis, and interpretation of data.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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