ReviewLessons learned from mice and man: Mimicking human allergy through mouse models
Section snippets
Disparities between human and mouse studies
Natural variants and genetic manipulation of various mouse strains, in the context of autoimmune susceptible backgrounds, have revealed key factors that contribute to common immune disorders. Origins of novel treatments for autoimmune pathologies are largely based on mouse models, thereby underscoring the importance of factors such as, but not limited to, IL-1 (Anakinra), IL-6 (Tocilizumab), TNFα (Etanercept), CD20 (Rituximab), IL-17 (Brodalumab). Data gleaned from these mouse models highlights
Human allergy
Allergy is an atopic immunologic syndrome characterized by an aberrant response to innocuous environmental antigens, specifically polarization toward a type 2T helper (TH2) cell-mediated immune response. Originally evolved to ward off extracellular helminth infections, allergic responses manifest as atopic dermatitis, asthma, food, insect and drug hypersensitivities, and allergic rhinitis [5]. Clinical presentations of allergy include airway hyper-responsiveness [8], pruritic rashes, urticaria,
Atopic dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a chronic inflammatory skin condition characterized by persistent pruritic rash and hypersensitivity to environmental antigens [26], [27]. Predominantly affecting young children and a fraction of patients with ichthyosis vulgaris (IV) [28], an autosomal dominant skin disorder characterized by dry, scaly patches, AD is characterized by CD4+ T-cell infiltrate, extensive keratosis, epithelial hyperplasia and remodeling, elevated IgE (total
Modeling outside–inside versus inside–outside AD development in mice
Due to a spontaneous mutation in the Flg gene, the flaky tail (Flgft) mouse mutant has been a powerful model for dissection of IV since the late 1960s. Flg codes the profilaggrin protein that is part of epithelial differentiation complex found in the stratum corneum and is necessary for the prevention of water loss and for the maintenance of barrier function against microbes. Flgft mice exposed at the epidermis to various environmental allergens generate AD-like symptoms in mice [59], [60]. The
Asthma: airway manifestation of atopy
Recurrent attacks of breathlessness, wheezing, and cough due to airway obstruction are hallmark features of asthma [5], [78], [79], [80]. Exposure to environmental allergens such as pollen, mold, grasses, insects and animal dander induce bronchial hyperresponsiveness, elevated granulocytic counts in the sputum, increased exhaled NOS levels and elevated levels in serum IgE and periostin. Upon repeated exposure of allergens, the bronchial lining is characterized by epithelial metaplasia, mucus
Asthma mouse models emphasize late-phase TH2 responses
Most experimental asthmatic mouse models use clonal mouse strains treated intraperitoneally (i.p.) with ovalbumin (OVA) and then exposed to aerosolized protein antigen OVA over an extended duration. These models highlight the importance of TH2 cytokines, alarmin proteins, ILC2s, IL-9, and Treg cells in a chronic inflammatory setting [94], [95], [96], [97], [98]. IL-4, IL-13 and IL-9 have similar responses in human and mice, but IL-5 remains controversial. Finkelman et al. provide a nice
Food allergy and other contact hypersensitivities
Food allergies (FA) are adverse health responses upon exposure to a given food allergen (processed, semi-processed, or raw) that triggers specific immune responses (IgE-mediated, non-IgE-mediated, or a combination of IgE-and non-IgE-mediated) and are reproducible upon repeated food exposure [116], [117]. Food allergies differ from food intolerances, which are non-immune responses to metabolites, toxins, pharmacologic and other idiopathic agents. FA are currently managed by strict avoidance of
Systemic and localized anaphylactic mouse models: replication of food and insect allergies
Early mouse models examining passive systemic anaphylaxis reveal the existence of IgE-dependent and IgG-dependent mechanisms of anaphylaxis [129]. The classical pathway leads to shock through a rapid and transient IgE-mediated response in mice after a low dose of antigen administration. Cross-linking of pre-bound IgE by antigen activates mast cells and basophils to degranulate vasoactive mediator histamine and induces vascular permeability, all of which culminates in hypotension and
Human and mouse studies reveal the importance of basophils and TSLP in EoE, but not IgE
EoE is a chronic TH2-driven inflammatory response localized to the esophagus and exacerbated by food allergens. Characterized by eosinophil accumulation, epithelial hyperplasia, extensive fibrosis, and stricture formation, EoE impairs food ingestion due to food impaction and vomiting, resulting in a failure to thrive [146], [147]. Diagnosis depends on clinical history and pathology and currently no treatments exist except for removal of causative food allergens. IL-5 and T-cells play a role in
Allergic rhinitis and chronic rhinosinusitis
Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) comprise two inflammatory diseases of the upper airways residing in the nasal passages and surrounding sinus tissue. As with asthma, AR and CRS exhibit both IgE-mediated and non-IgE immune responses that manifest as different endotypes [155]. AR often predisposes patients to progress to CRS, both of which often coexist with asthma as part of the atopic march hypothesis [156], [157]. Similar triggers between AR, CRS and asthma induce a
Modeling AR and CRS as a continuum of asthma
Analysis of upper airway inflammation relies chiefly on OVA-sensitization subcutaneously (s.c.) or i.p. and subsequent large dose OVA challenge as seen in asthma mouse models. Considering that asthma and AR/CRS often coexist and several studies suggest that AR and asthma are a continuum [168], it is likely that application of asthma mouse models will address similar questions for AR research. Recent methods improve upon older mouse models of AR, by using small doses of aerosolized OVA for
Concluding remarks
One of the primary aims in translational medicine is the development of therapies and diagnostics. Current therapies in the pipeline derived from mouse models include Mepolizumab (αIL-5 monoclonal) [171], Dupilumab (αIL-4Rα monoclonal — blockade against the common receptor component to IL-4 and IL-13 signaling) [172], [173], and AMG 157 (αTSLP monoclonal) [174] and have demonstrated encouraging results in Phase I and II human trials. Mouse models have provided extensive understanding of
Conflicts of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgments
The authors thank Monali Manohar, PhD and Kimberly Vu, BS for the manuscript critique and editing. This work is supported by the Child Health Research Institute, Lucile Packard Foundation for Children's Health, and Stanford CTSA (grant #: UL1 TR001085).
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2016, Journal of Controlled ReleaseCitation Excerpt :Transgenic and knockout models may be more useful for studying a particular pathway of the COPD pathogenesis, as exact roles of specific genes can be elucidated in these models. The ovalbumin (OVA)-challenged mouse model is by far the most widely utilized preclinical model for allergic asthma, exhibiting the characteristic Th2-type immune response [399]. The models are generally established by intraperitoneal sensitization with OVA, followed by repeated intratracheal OVA challenges, but exact dosing schedule varies among individual studies [400].