Elsevier

Clinical Immunology

Volume 155, Issue 1, November 2014, Pages 1-16
Clinical Immunology

Review
Lessons learned from mice and man: Mimicking human allergy through mouse models

https://doi.org/10.1016/j.clim.2014.08.002Get rights and content

Highlights

  • Inflammatory responses differ between mouse and man.

  • These differences present a challenge in modeling human disease.

  • Inadequate characterization of allergy limits generation of better mouse models.

  • Genetic manipulation of mice highlights key contributors to allergy.

  • Enhanced characterization of clinical disease improves modeling of allergy in mouse.

Abstract

The relevance of using mouse models to represent human allergic pathologies is still unclear. Recent studies suggest the limitations of using models as a standard for assessing immune response and tolerance mechanisms, as mouse models often do not sufficiently depict human atopic conditions. Allergy is a combination of aberrant responses to innocuous environmental agents and the subsequent TH2-mediated inflammatory responses. In this review, we will discuss current paradigms of allergy — specifically, TH2-mediated and IgE-associated immune responses — and current mouse models used to recreate these TH2-mediated pathologies. Our overall goal is to highlight discrepancies that exist between mice and men by examining the advantages and disadvantages of allergic mouse models with respect to the human allergic condition.

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).

References (177)

  • H. Fujita

    The role of IL-22 and Th22 cells in human skin diseases

    J. Dermatol. Sci.

    (2013)
  • L. Pellerin et al.

    Defects of filaggrin-like proteins in both lesional and nonlesional atopic skin

    J. Allergy Clin. Immunol.

    (2013)
  • J.N. Barker et al.

    Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood

    J. Invest. Dermatol.

    (2007)
  • S.P. Saunders et al.

    Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects

    J. Allergy Clin. Immunol.

    (2013)
  • A. Rebane et al.

    Mechanisms of IFN-γ-induced apoptosis of human skin keratinocytes in patients with atopic dermatitis

    J. Allergy Clin. Immunol.

    (2012)
  • A. De Benedetto et al.

    Tight junction defects in patients with atopic dermatitis

    J. Allergy Clin. Immunol.

    (2011)
  • H. Kinoshita et al.

    Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA

    J. Allergy Clin. Immunol.

    (2009)
  • T. Savinko et al.

    IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors

    J. Invest. Dermatol.

    (2012)
  • J. Verhagen et al.

    Absence of T-regulatory cell expression and function in atopic dermatitis skin

    J. Allergy Clin. Immunol.

    (2006)
  • T. Volz et al.

    Nonpathogenic bacteria alleviating atopic dermatitis inflammation induce IL-10-producing dendritic cells and regulatory Tr1 cells

    J. Invest. Dermatol.

    (2014)
  • C.S. Moniaga et al.

    Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus extract

    Am. J. Pathol.

    (2010)
  • J.M. Leyva-Castillo et al.

    TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice

    J. Invest. Dermatol.

    (2013)
  • S.F. Ziegler et al.

    The biology of thymic stromal lymphopoietin (TSLP)

    Adv. Pharmacol.

    (2013)
  • S.R. Wilson et al.

    The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch

    Cell

    (2013)
  • M. Li et al.

    Induction of thymic stromal lymphopoietin expression in keratinocytes is necessary for generating an atopic dermatitis upon application of the active vitamin D3 analogue MC903 on mouse skin

    J. Invest. Dermatol.

    (2009)
  • D.A. Searing et al.

    Vitamin D in atopic dermatitis, asthma and allergic diseases

    Immunol. Allergy Clin. N. Am.

    (2010)
  • L.J. Yockey et al.

    The absence of a microbiota enhances TSLP expression in mice with defective skin barrier but does not affect the severity of their allergic inflammation

    J. Invest. Dermatol.

    (2013)
  • C. Corrigan

    Mechanisms of asthma

    Medicine

    (2012)
  • C. Seroogy et al.

    The role of T regulatory cells in asthma

    J. Allergy Clin. Immunol.

    (2005)
  • K. Nadeau et al.

    Ambient air pollution impairs regulatory T-cell function in asthma

    J. Allergy Clin. Immunol.

    (2010)
  • P. Blair et al.

    CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients

    Immunity

    (2010)
  • W. van de Veen et al.

    IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses

    J. Allergy Clin. Immunol.

    (2013)
  • J. Seok et al.

    Genomic responses in mouse models poorly mimic human inflammatory diseases

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • A.R. Osterburg et al.

    Concerns over interspecies transcriptional comparisons in mice and humans after trauma

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • N. de Souza

    Model organisms: mouse models challenged

    Nat. Methods

    (2013)
  • J. Mestas et al.

    Of mice and not men: differences between mouse and human immunology

    J. Immunol.

    (2004)
  • F.D. Finkelman et al.

    Importance of cytokines in murine allergic airway disease and human asthma

    J. Immunol.

    (2010)
  • N. Acevedo et al.

    Interaction between retinoid acid receptor-related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma

    PLoS One

    (2013)
  • S.H. Sicherer et al.

    Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2012

    J. Allergy Clin. Immunol.

    (2012)
  • A. Syed et al.

    Food allergy diagnosis and therapy: where are we now?

    Immunotherapy

    (2013)
  • P.S. Gao et al.

    Genetic variants in thymic stromal lymphopoietin are associated with atopic dermatitis and eczema herpeticum

    J. Allergy Clin. Immunol.

    (2010)
  • S. Ying et al.

    Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease

    J. Immunol.

    (2008)
  • S. Ying et al.

    Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity

    J. Immunol.

    (2005)
  • W. Tang et al.

    IL-25 and IL-25 receptor expression on eosinophils from subjects with allergic asthma

    Int. Arch. Allergy Immunol.

    (2014)
  • M. Fux et al.

    IL-33 is a mediator rather than a trigger of the acute allergic response in humans

    Allergy

    (2014)
  • M. Noti et al.

    Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis

    Nat. Med.

    (2013)
  • W. Yao et al.

    Predisposition to the development of IL-9-secreting T cells in atopic infants

    J. Allergy Clin. Immunol.

    (2011)
  • C.N. Palmer et al.

    Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

    Nat. Genet.

    (2006)
  • M. Jutel et al.

    Immunological mechanisms of allergen-specific immunotherapy

    Allergy

    (2011)
  • M. Boguniewicz et al.

    Atopic dermatitis: a disease of altered skin barrier and immune dysregulation

    Immunol. Rev.

    (2011)
  • Cited by (24)

    • PAR2 Pepducin-Based Suppression of Inflammation and Itch in Atopic Dermatitis Models

      2019, Journal of Investigative Dermatology
      Citation Excerpt :

      Accumulating research implicates PAR2 as a major contributor to atopic dermatitis, a chronic inflammatory skin disease affecting over 32 million people with a prevalence of 10% in the United States (Silverberg and Hanifin, 2013). As an atopic response to environmental allergens, atopic dermatitis skin lesions in both humans and mice involve enhanced inflammatory networks that are largely driven through T-cell–dependent recruitment and degranulation of mast cells, basophils, and eosinophils (Graham and Nadeau, 2014). Atopic dermatitis is typically treated with steroids or calcineurin inhibitors to suppress mast cell and T-cell activation; however, these therapies are often not fully effective and carry the risk of adverse effects, especially when used long-term or in children (Eichenfield et al., 2017; Frankel and Qureshi, 2012).

    • Immunologic, microbial, and epithelial interactions in atopic dermatitis

      2018, Annals of Allergy, Asthma and Immunology
      Citation Excerpt :

      The fact that AD is primarily a T-cell–driven disease49,50 has been proven by the therapeutic efficacy of T-cell targeting agents such as cyclosporine, efalizumab, and alefacept.51–53 Because no single animal model reflects the complex phenotype of AD, clinical trials using targeted therapeutics in humans are mandatory to fully understand this disease.54–56 Broadly immunosuppressive therapies such as cyclosporine A, systemic corticosteroids, and narrowband ultraviolet B have been used for decades to treat moderate-to-severe AD, but their advent is based more on serendipity than on a detailed understanding of their mode of action.57

    • A distinct microbiota composition is associated with protection from food allergy in an oral mouse immunization model

      2016, Clinical Immunology
      Citation Excerpt :

      Therefore, researchers have focused on identifying underlying mechanisms of food allergy development using animal models. Although substantial differences are known between human and mouse allergic responses, food allergy mouse models provide important and useful information on disease mechanisms [26,27]. However, a number of different routes and protocols of sensitizations has been published so far, rendering direct comparison of results from studies highly complex [28].

    • Barriers to inhaled gene therapy of obstructive lung diseases: A review

      2016, Journal of Controlled Release
      Citation 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].

    View all citing articles on Scopus
    View full text