Fischer, Romy (2005) Mouse models of peanut allergy Contribution of oral and nasal sensitization to allergic reactions to peanut and cross-reactivity with food and environmental antigens. PhD thesis Biologie cellulaire et moléculaire, Unité INRA de physiologie de la nutrition et de l'intestin, INAPG 2005INAP0011.

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Abstract

Food-allergic patients can develop adverse reactions to members of the same and even unrelated botanical families. IgE and Th2-type responses play an important role in allergic reactions although it is now clear that these reactions involve other cellular and molecular interactions. We investigated the role played by the mucosal sites of initial priming to peanut on subsequent immune responses to peanut and reactivity to airway antigen challenge. For this purpose, we analyzed antibody responses to peanut immunization, as well as cytokine and airway responses to nasal antigen challenge in mice orally or nasally sensitized to peanut in the presence of cholera toxin. Oral peanut sensitization induced higher levels of IgE but lower IgG responses than nasal immunization. Both mice sensitized orally and nasally to peanut experienced airway hyper-reactivity upon nasal peanut challenge. However, orally sensitized mice exhibited higher levels of lung eosinophilia and IL-4 in response to peanut challenge. In contrast, higher levels of lung MAC-1+ cells and inflammatory cytokines were seen in nasally sensitized mice. Finally, nasal but not oral sensitization promoted lung inflammatory responses to unrelated antigens. These findings suggest that the initial route of sensitization influence the responses of peanut allergic individuals to airborne antigens and allergens.

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Table of content

􀂃 ABSTRACT

􀂃 FIGURE LIST AND ABBREVIATIONS

􀂃 INTRODUCTION

1. Food allergies 1

1.1. Definition and incidence of food allergies 1

1.2. Classes of food allergies 3

1.2.1. Class 1 or true food allergy 3

1.2.1.1. Main allergens and clinical symptoms 3

1.2.1.2. Cross-reactivity between food allergens 5

1.2.2. Class 2 or pollen-associated food allergy 5

1.3. Cellular and molecular mechanisms of food allergy 7

1.3.1. Th1 and Th2 cell subsets and responses 7

1.3.2. Allergic reaction to a primary allergen 9

1.3.2.1. Basic mechanisms of allergy: the Th2 hypothesis 9

1.3.2.2. Food allergy as a polyphenotypic disease 10

1.3.2.2.1. Data supporting the Th2 hypothesis 10

1.3.2.2.2. Role of Th1 cells in food allergy 12

1.3.2.2.3. Regulation of the immune response to dietary antigens 13

1.4. Cross-reactive allergic reaction 15

1.4.1. Antibody cross-reactivity 15

1.4.1.1. Molecular basis: structural identity between allergens 15

1.4.1.2. Cross-reactive protein epitopes 15

1.4.1.3. Cross-reactive carbohydrate epitopes 16

1.4.2. Induction of cross-reactive allergic symptoms by B and mast cell triggering 16

1.4.2.1. B cell triggering by a cross-reactive allergen 16

1.4.2.2. Mast cell triggering by a cross-reactive allergen 18

1.4.3. Basis for discrepancies between in vitro and clinical tests 18

1.4.3.1. Monovalent CCDs 19

1.4.3.2. Low-affinity antibodies 19

1.4.3.3. IgE assays and detection of cross-reactive antigens 19

2. Interplay between the GI and respiratory tracts in food allergy 22

2.1. Asthma induced by food ingestion or food inhalation 22

2.2. GI and respiratory tracts as sites of sensitization and reactivity to food allergens 23

2.2.1. NALT and PP's: morphologic and functional similarities 23

2.2.2. Distinct features of NALT and Peyer's patches 24

2.3. Mechanism of food-induced asthma 26

2.3.1. IgE-mediated asthma 26

2.3.2. Non-IgE-mediated asthma 28

3. Food allergy in the legume family 29

3.1. Peanut and lupine as primary allergens 29

3.1.1. Primary allergy to peanut 29

3.1.2. Primary allergy to lupine 30

3.1.2.1. Lupine in human consumption 30

3.1.2.2. Lupine allergens 30

3.1.2.3. Case reports of allergic reactions to lupine 31

3.2. Cross-reactivity between peanut and other legumes 32

3.2.1. Cross-reactivity in the legume family is clinically irrelevant in most cases 32

3.2.2. Some particular legumes may favor cross-reactive reactions 33

3.3. Peanut allergy and asthma 34

3.3.1. Aerosolized peanut as an allergic reaction-trigger 34

3.3.2. Aerosolized peanut as a sensitizing agent 35

4. Animal models of food allergy 36

4.1. Models to investigate mechanisms of food allergies 37

4.1.1. Studies in mice 37

4.1.1.1. Advantages and limitations of the mouse model of food allergy 37

4.1.1.2. Dissecting mechanisms: systemic sensitization / OVA + alum 38

4.1.1.3. Mimicking human food allergy: oral sensitization / protein extract + CT 38

4.1.2. Studies in nonrodent animals 39

4.1.2.1. The atopic dog model 39

4.1.2.2. The swine model 40

4.2. Models to predict the allergenicity of novel proteins 40

4.2.1. Advantages of animal models compare to in vitro studies 40

4.2.2. Studies in the Brown Norway rat: oral sensitization / no adjuvant 41

4.2.3. Studies in BALB/c: intraperitoneal sensitization / no adjuvant 41

4.3. Conclusion 42

􀂃 MATERIAL AND METHODS 43

Peanut and legume extracts 44

Mice 45

Mucosal immunizations 45

Nasal challenge with peanut and unrelated proteins 46

Plasma antibody responses 46

Airway hyper-reactivity 48

Histology and determination of lung inflammation scores 50

Flow cytometry 51

Purification of CD4+ T cells 52

Quantification of cytokine and chemokine mRNA by real-time PCR 52

Bronchoalveolar lavage and cytospin 53

Cytokine ELISA 53

Statistics 54

􀂃 RESULTS 55

1. Proteins in peanut and legume extracts 57

2. Reactivity of anti-peanut Abs against legumes 57

3. Role of mucosal routes of sensitization in peanut-specific Ab responses 61

The nasal route of immunization 63

The oral route of immunization 63

4. Influence of the mucosal route of sensitization on airway responses to secondary exposure to peanut 70

Both nasally and orally sensitized mice experienced AHR after nasal peanut challenge 70

Nasal and oral sensitization promoted distinct lung responses to secondary exposure to peanut 74

Phenotype of lung mononuclear cells after nasal peanut challenge 77

5. Distinct Th cell and inflammatory cytokine responses in mice sensitized by the oral or nasal routes 78

Nasal peanut challenge induces higher Th2-type cytokine responses in orally sensitized mice 78

Role of Th1 and Th2 cytokines in the Ab response to peanut sensitization 80

Antibody responses in C57BL/6 WT and IL-4 KO mice 80

Antibody responses in BALB/c WT and IL-4/IL-13 KO mice 82

Antibody responses in C57BL/6 WT, IL-12p40 KO and IFN-γ KO mice 84

Role of Th1 and Th2 cytokines in lung inflammatory responses to peanut challenge 86

Lung inflammatory responses in IL-4 KO and IL-4/IL-13 double KO mice 86

Lung inflammatory responses in IL-12 KO and IFN-g KO mice 88

6. Biological significance of immune responses induced by oral vs nasal sensitization 90

In vitro reactivity of Abs from mice nasally or orally sensitized to peanut with legumes or unrelated antigens

90Differential lung responses to nasal challenge with legumes or unrelated antigens 92

Recruitment of lung MAC-1+ cells after nasal challenge with legumes or unrelated antigens 92

􀂃 DISCUSSION AND CONCLUSION - 96-112

􀂃 REFERENCES - 115-135

􀂃 PUBLICATIONS AND COMMUNICATIONS - 136

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