Establishment and characterization of a murine model for allergic dermatitis and asthma using dermatophagoides mite allergens

ESTABLISHMENT AND CHARACTERIZATION OF A MURINE MODEL FOR ALLERGIC DERMATITIS AND ASTHMA USING DERMATOPHAGOIDES MITE ALLERGENS HUANG CHIUNG-HUI (MSc, National Taiwan University, Taiwan) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PAEDIATRICS NATIONAL UNIVERSITY OF SINGAPORE 2004 i Acknowledgments I would like to express my sincere appreciation to the following who had been instrumental in the accomplishment of this study. To my supervisor, Professor Chua Kaw Yan, for her invaluable guidance and patience through out the conduct of my PhD project. To Dr. Keli Ou and Professor Lee Yoke Sun for their advice and technical assistance. To Drs. Cheong Nge, Liew Lip Nyin, Kuo I-Chun, and Lynette Shek, for their discussion and assistance in the writing of this thesis. To the members of Asthma and Allergy Research Laboratory, Ms Yi Fong Cheng, Ms Tan Li Kiang, Ms Xu Hui, Ms Wen HongMei, Ms Liew Lee Mei, Mr Seow See Voon, for their supports. Last but not least, to my parents and my siblings for their love, trust and constant encouragement. ii List of Publications Publications derived from this thesis Huang CH, Kuo IC, Xu H, Lee YS, Chua KY. Mite allergen induces allergic dermatitis with concomitant neurogenic inflammation in mouse. J Invest Dermatol. 2003;121:289-93. Huang CH, Liew LM, Mah KW, Kuo IC, Lee BW, Chua KY. Characterization of glutathione S-transferase (GST) from dust mite, Der p and its IgE cross-reactivity with cockroach GST. (submitted) Publications in the related fields Yang L, Cheong N, Wang DY, Lee BW, Kuo IC, Huang CH, Chua KY Generation of monoclonal antibodies against Blo t using DNA immunization with in vivo electroporation. Clin Exp Allergy. 2003;33:663-8. iii Table of Contents Title page Acknowledgements List of publication Tables of contents List of Figures List of Tables List of Abbreviations Summary Chapter Literature review 1.1. Immunoglobulin E 1.1.1 Signals involved in IgE production 1.1.2 Receptors for IgE 1.1.2.1 FcεRI 1.1.2.2 FcεRII 1.2. Development of Th1/Th2 cells 1.2.1 Nature of the interaction of the T-cell receptor with MHC-peptide complex 1.2.2 APCs and costimulatory molecules 1.2.2.1 CD28/CTLA-4/ICOS/PD-1 and B7 family 1.2.2.2 Dendritic cells 1.2.3 Cytokine and transcription factors 1.2.3.1 Th1 development 1.2.3.2 Th2 development 1.3. House dust mite allergens 1.4. Atopic dermatitis 1.4.1 Epidemiology 1.4.1.1 Natural History 1.4.1.2 Prevalence 1.4.1.3 Risk factors 1.4.2 Environmental triggers of atopic dermatitis 1.4.2.1 Allergens 1.4.2.1.1 Aeroallergens 1.4.2.1.2 Food allergens 1.4.2.2 Microorganisms 1.4.2.3 Autoantigen 1.4.2.4 Other environmental triggers 1.4.3 Immunopathogenesis of atopic dermatitis 1.4.3.1 Skin homing T cell and atopic dermatitis 1.4.3.2 Biphasic cytokine expression pattern in atopic dermatitis skin lesions 1.4.3.3 Mechanism of chronic skin inflammation 1.4.3.4 Other cells involved in immunopathogenesis of atopic dermatitis 1.4.3.4.1 Dendritic cells 1.4.3.4.2 Monocytes 1.4.3.4.3 Keratinocytes i ii iii ix viii x xi xiii 1 3 10 11 12 13 14 15 21 21 21 22 24 26 26 26 28 29 31 31 32 33 34 35 36 36 37 38 iv 1.4.3.4.4 Eosinophils/Mast cells 1.4.3.5 Skin Barrier and atopic dermatitis 1.4.3.6 Neuroimmunologic factors 1.5. Murine models of atopic dermatitis 1.5.1 Percutaneous sensitization mouse model 1.5.2 Epicutaneous sensitization mouse model 1.5.3 NC/Nga mice 1.5.4 Humanized severe combine immunodeficiency model 1.5.5 Systemic Immunization 1.5.6 relB-/- mice Chapter 2. Rationales and Specific Aims of the Study 2.1 Rationales of the study 2.2 Specific aims of the study Chapter 3. Characterization of glutathione S-transferase (GST) from dust mite, Der p and its IgE cross-reactivity with cockroach GST 3.1. Introduction 3.2. Materials and Methods 3.2.1 Cloning of Der p gene 3.2.2 Expression of recombinant Der p and recombinant Sj26 3.2.3 Purification of native Der p and native Der p 3.2.4 Cockroach allergens 3.2.5 Sera 3.2.6 2-D electrophoresis and Western blotting 3.2.7 MALDI-TOF mass spectrometry 3.2.8 Determination of antigen specific IgE by ELISA 3.2.9 Inhibition study 3.2.10 Statistic analysis 3.3. Results 3.3.1 Sequence analysis of cDNA coding for Der p 3.3.2 SDS-PAGE analysis of native and recombinant Der p 3.3.3 Presence of isoforms in native Der p 3.3.4 Comparison of IgE reactivity to recombinant Der p and native Der p 3.3.5 Presence of IgE cross-reactivity between Der p and cockroach GST 3.3.6 Comparison of IgE reactivity to rDer p and Sj26 3.4. Discussions Chapter Mite allergen induces atopic dermatitis and allergic asthma with concomitant neurogenic inflammation in mouse 4.1 Introduction 4.2 Materials and Methods 4.2.1 Mice and antigens 4.2.2 Expression of OVA in Pichia pastoris 4.2.3 Antibodies 4.2.4 Mice sensitization and challenge protocols 4.2.5 Detection of antigen specific mouse immunoglobulin responses 4.2.6 Preparation of single cell suspension 39 40 41 43 43 44 45 46 47 47 49 49 53 54 54 57 57 57 58 59 59 60 60 61 62 62 63 63 63 64 64 65 66 77 83 83 85 85 85 85 86 87 88 v 4.2.7 Short-term T cell culture in vitro 4.2.8 Preparation of antigen presenting cells 4.2.9 Separation of dead cells from short-term cultured splenocytes by Ficoll-Paque centrifugation 4.2.10 Measurement of cell proliferation by [3H]-Thymidine incorporation 4.2.11 Purification of CD4+ and CD8+ T cells by AutoMACS 4.2.12 Stimulation of T cells by anti-CD3 and anti-CD28 mAbs 4.2.13 Cytokine ELISA 4.2.14 Intracellular staining 4.2.15 Histocytochemistry and Immunocytochemistry 4.2.16 Non-invasive measurement of airway responsiveness 4.2.17 Collection of bronchoalveolar lavage and cytospin preparation for differential cell counts 4.2.18 Data analysis 4.3 Results 4.3.1 Epicutaneous sensitization of Der p induced specific cellular and humoral immune response in mice 4.3.2 Comparison of antibody responses between OVA and Der p sensitized mice 4.3.3 OVA induced mild pathological changes in the skin 4.3.4 Der p induced severe dermatitis 4.3.5 Evaluation of the immune response induced by native OVA (OVA) and recombinant OVA (rOVA) 4.3.6 Th2 skewed cytokine profiles induced by epicutaneous sensitization of Der p 4.3.7 Cytokines profiles of T- subsets 4.3.8 A systemic type 2-immune response induced by epicutaneous sensitization of Der p 4.3.9 Epicutaneous sensitization induced airway inflammation 4.3.10 Interaction between neuropeptides and immune target cells 4.4 Discussions Chapter Comparison of responses induced by epicutaneous patching with allergenic and nonallergenic proteins 5.1 Introduction 5.2 Materials and Methods 5.2.1 Antigens 5.2.2 Sensitization and challenge of mice 5.2.3 Measurement of airway hyperresponsiveness and collection of bronchoalveolar lavage 5.2.4 Splenocytes culture in vitro 5.2.5 Detection of antibodies in sera and cytokines in culture supernatants 5.2.6 Preparation of dermal fibroblast 5.2.7 Stimulation of fibroblast with different stimulants 5.2.8 Detection of eotaxin by ELISA 5.2.9 RNA extraction 5.2.10 Real-time RT-PCR for IL-5 5.2.11 Detection of chemokines in fibroblasts by RNase protection 88 89 89 89 90 90 91 91 92 93 94 94 95 95 95 96 96 97 98 99 100 101 101 126 133 133 136 136 136 136 136 137 137 138 138 139 139 vi assay 5.3 Results 5.3.1 Induction of specific humoral responses in mice patched with Der p and Fve 5.3.2 Induction of specific cellular responses in mice patched with Der p and Fve 5.3.3 Histopathology of the patched skins 5.3.4 In-vitro studies to examine the interaction of antigen and dermal fibroblasts 5.3.4.1 Expression of IL-5 mRNA by antigen stimulated dermal fibroblasts 5.3.4.2 Eotaxin production by dermal fibroblasts 5.3.4.3 Expression of MCP-1 mRNA by dermal fibroblasts 5.3.4.4 Expression of MCP-1α and MCP-2 mRNA by dermal fibroblasts 5.3.5 Induction of airway inflammation and hyperresponsiveness in mice patched with Der p and Fve 5.4 Discussions 140 144 144 144 146 146 147 147 148 148 149 162 Chapter Conclusions and Future Prospects 170 Chapter References 176 vii List of Figures Figure 3.1 Nucleotides and amino acid sequences alignment of two Der p 67 isoforms. Figure 3.2. Sequence alignment of dust mite GST (Der p 8), cockroach GST 68 (Bla g 5) and parasite GST (Sj26). Figure 3.3 SDS-PAGE analysis of recombinant and native Der p 8. 69 Figure 3.4 Characterization of nDer p by two-dimensional electrophoresis. 70 Figure 3.5 Comparison of erDer p 8, yrDer p and nDer p specific IgE 71 among the Taiwanese sera Figure 3.6 Correlation of IgE titer of recombinant Der p and native Der p 72 8. Figure 3.7 Comparison of nDer p and nDer p specific IgE titer in 73 Taiwanese sera. Figure 3.8 Comparison of nDer p specific IgE titer among Taiwanese, 74 Malaysian and Singaporean. Figure 3.9 Presence of cross-reactive IgE between nDer p and cockroach 75 GST. Figure 3.10. Comparison of Sj26 and nDer p specific IgE titer in Taiwanese 76 sera. Figure 4.1 Total IgE and T cell responses in mice sensitized with Der p by 103 epicutaneous patching. Figure 4.2 Specific antibody responses in mice sensitized with Der p by 104 epicutaneous and inhalation routes. Figure 4.3. Comparison of specific antibodies response in mice 105 epicutaneously sensitized with Der p or OVA. Figure 4.4. Skin histopathology induced by OVA. 106 Figure 4.5. Skin histopathology induced by Der p 8. 107 Figure 4.6. Der p sensitization induced infiltration of T cells and dendritic 108 cells. Figure 4.7. Expression of recombinant OVA in Pichia pastoris. 109 Figure 4.8. Comparison of specific antibody responses in mice sensitized 110 with recombinant OVA or native OVA by epicutaneous route. Fig ure 4.9. Skin histopathological features in mice sensitized with 111 viii recombinant OVA or native OVA by epicutaneous route. Figure 4.10. Production of Th2-skewed cytokines by splenocytes in mice 112 sensitized with Der p by epicutaneous route. Figure 4.11. Production of Th2-skewed by cultured T cells of Der p patched 113 mice. Figure 4.12. Increment of CD8+ T cells in the cultured T cells of Der p 114 patched mice. Figure 4.13. Intracellular cytokine staining of CD4+ and CD8+ T cells subsets. 115 Figure 4.14. Cytokine production by CD4+ T cells. 116 Figure 4.15. Cytokine production by CD8+ T cells. 117 Figure 4.16. Production of IL-10 and IL-13 in Der p patched mice. + + 118 Figure 4.17. Intracellular IL-10 staining CD4 and CD8 T cell subsets. 119 Figure 4.18. Systemic enhancement of Th2 cytokines in mice sensitized with 120 Der p by epicutaneous route. Figure 4.19. Induction of airway inflammation and hyperresponsiveness in Der 121 p patched mice after intratracheal challenge with Der p 8. Figure 4.20. Histocytochemical staining of mast cells (I). 123 Figure 4.21. Histocytochemical staining of mast cells (II). 124 Figure 4.22. Immunohistochemical staining of neuropeptides. 125 Figure 5.1. 151 Humoral immune responses in mice sensitized with Der p or Fve by epicutaneous patching. Figure 5.2. Production of cytokines by splenocytes in mice sensitized with 152 Der p or Fve. Figure 5.3 Production of cytokines by secondary T lymphocytes. 153 Figure 5.4 Histopathology of PBS, Der p and Fve patched skins. 154 Figure 5.5. Cultured dermal fibroblasts. 155 Figure 5.6. The expression of IL-5 mRNA by fibroblasts in the absence or 156 presence of various antigens. Figure 5.7 Eotaxin production by dermal fibroblasts. 157 Figure 5.8. MCP-1 mRNA expression by dermal fibroblasts. 158 Figure 5.9. MIP-1α and MIP-2 mRNA expression by dermal fibroblasts. 159 Figure 5.10. Airway hyperresponsiveness in Der p and Fve-patched mice. 160 Figure 5.11. Differential cell counts of bronchoalveolar larvage fluids 161 ix List of Tables Table 1.1 Summary of denominated HDM allergens 20 Table 1.2 Trends in the lifetime prevalence of atopic dermatitis in children 22 born between 1960 and 1993 Table 1.3. Prevalence surveys of atopic dermatitis in children born after 23 1980 Table 4.1. 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EMBO J. 1993;12:2663-2670. 208 [...]... itching and a chronic relapsing course The concept of “atopy” (derived from the Greek atopia, meaning “different” or “out of place”) was originally proposed in 1923 to include asthma and allergic rhinitis, but AD was added to the group of atopic disorder in 1933 on the basis of association of this form of eczema with asthma and allergic rhinitis In fact, AD is most often the first manifestation of this atopic... allergens to establish a murine model for allergic dermatitis and asthma through skin sensitization, and to further exploit the model for mechanistic studies The first part of this study focused on the cloning and characterization of a new isoform of Der p 8, a glutathione-S-transferase (GST), from Dermatophagoides pteronyssinus mites This isoform represents one of the variants found in native Der p 8 IgE... asthma (ISAAC steering committee et al., 199 8a; Gustafsson D et al., 2000; Rhodes HL et al., 2001 & 2002; Lau S et al., 2002; Ohshima Y et al., 2002;) These results also demonstrated that the severity of AD was a risk factor for subsequent development of asthma and allergic rhinitis Approximately 60% of patients experience the development of signs of AD before their first birthday, and another 30% of patients... allergic asthma, atopic dermatitis and allergic rhinitis are increasing worldwide House dust mites allergy is strongly associated with these allergic diseases The skin is thought to be the primary entering site of allergens as the symptom of atopic dermatitis usually develops before asthma and rhinitis but the underlying mechanisms remain unresolved This study aimed to use house dust mite allergens to establish... both mites and cockroaches are important sources of indoor allergens The second part of the study was to establish a mouse model for atopic dermatitis / asthma using recombinant Der p 8 by epicutaneous sensitization approach Der p 8patched mice showed elevated total IgE and low but significant levels of specific IgE that were boostable by airway allergen challenge Splenic T cells produced typical xiii...Abbreviations AD atopic dermatitis Ag Antigen AHR airway heperresponsiveness APC antigen presenting cell BAL bronchoalveolar lavage Bla g Blagttella germanica CD cluster of differentiation cDNA complimentary DNA CGRT calcitonin gene-related peptide CHAPS 3-[(3-cholamidopropul)dimethylammoniol]-1-propanesulphonate CLA cutaneous lymphocyte antigen Conc concentration cpm count per minute CTLA-4 Cytotoxic... the presence of IL-4 and antibodies against IL-12 or IFN-γ), the IL-4 signaling factor STAT6 is activated, which translocates into the nucleus and rapidly induces (either directly or indirectly) the expression of GATA-3 (Ouyang W et al., 1998; Kurata H et al., 1999) GATA-3 is a Th2 cell-specific transcription factor and is a master regulator of the Th2 differentiation pathway (Zhang DH et al., 1997;... role of mucosal tissue cells in inflammatory responses This work supports the notion that the skin is an important site for the initiation of primary allergen sensitization and subsequent development of systemic allergic reactions verifying the concept of “atopic march” This model is useful for basic studies of immunopathogenesis of AD and asthma It is also useful for study of other stress-associated... Der p 3, Der f 3 and Eur m 3 (Cheong N et al., 2003) Der p 3 and Der f 3 also had polymorphic residues (Nishiyama C et al., 1995; Smith WA & Thomas WR, 199 6a & 1996b) The proteolytic activity of Der p 3 has been demonstrated to cleave the complements C3 and C5 and generate anaphylatoxins C 3a and C 5a (Maruo K et al., 1997) Group 9 allergen was only found in native form from Dermatophagoides pteronyssinus... reactivity of 40% (Tovey ER et al., 1989), however Blo t 5 of B tropicalis appeared to be a very important allergen as it reacted with 70% of sera (Arruda LK et al., 1995) Blo t 5 had 43% sequence 18 identity to Der p5 and little cross-reactivity (Kuo IC et al., 2003) One Der p 5 isoform was reported with a single amino acid variation of alanine to aspartate at position 61 (Lin KL et al., 1994) Native . ESTABLISHMENT AND CHARACTERIZATION OF A MURINE MODEL FOR ALLERGIC DERMATITIS AND ASTHMA USING DERMATOPHAGOIDES MITE ALLERGENS HUANG CHIUNG-HUI (MSc, National Taiwan University, Taiwan). TSLP stromal lymphopoetin VIP vasoactive intestinal peptide xiii Summary The prevalence of allergic diseases such as allergic asthma, atopic dermatitis and allergic rhinitis are increasing. before asthma and rhinitis but the underlying mechanisms remain unresolved. This study aimed to use house dust mite allergens to establish a murine model for allergic dermatitis and asthma through