Heat denaturation affects the ProDer p 1 IgE reactivity and downregulates the development of the specific allergic response☆

Magi, Mauro; Garcia, Lida; Vandenbranden, Michel; Palmantier, Rémi; Jacquet, Alain

doi:10.1016/j.jaci.2004.04.014

Cited by 19 publications

(19 citation statements)

References 51 publications

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“…This was previously reported for other allergens [25,26,32] and fits well with the clinical observations that allergic individuals usually tolerate cooked food better than raw food [25]. We also found that heat-denatured allergens showed a lower potential to sensitise mice.…”

Section: Discussionsupporting

confidence: 92%

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

et al. 2005

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Allergen-specific immunotherapy (SIT) leads to a long-term amelioration of IgE-and Th2-mediated allergic diseases. However, SIT efficiency is low, with years of treatment along with frequent allergic side effects. The goal of this study was to reduce the side effects by destroying IgE-binding epitopes, i.e. by heat-denaturation, while preserving the therapeutic effect. Mice were immunised with bee venom, birch pollen, grass pollen or cat hair allergens, or with ovalbumin. Heat-denatured allergens bound less IgE but enhanced Th1-dependent IgG2a production as measured by ELISA. The strong IgG2a antibody responses also prevented allergic anaphylaxis in mice, as measured by body temperature drop after a challenge with a high allergen dose. We found that optimal heat-denaturation of allergens left a small proportion in the native conformation to sufficiently stimulate B cells, while non-B cell-mediated effects were probably amplified. The enhanced immunogenicity of heat-denatured allergens is likely explained by enhanced antigen presentation to T cells due to the particulate nature of heat-denatured proteins. This enables Th1 skewing of the immune response with strong production of IgG2a in mice. Therefore, heat-denaturation represents probably the simplest way to enhance the efficiency of SIT while reducing its side effects. IntroductionIgE-mediated type I hypersensitivity is characterised by prominent activity of mast cells, eosinophils, T helper type 2 (Th2) cells and cytokine actions. Allergenspecific immunotherapy (SIT) leads to long-term amelioration of allergic symptoms and is therefore recommended as a first-line therapy for allergies [1]. During SIT, gradually increasing allergen doses are subcutaneously administered until a maintenance dose is reached, and then treatment continues for 3-5 years. Such lengthy treatment, requiring 30-80 allergen injections, is very costly [2]. Also, SIT frequently causes adverse events due to the interaction of specific IgE with the injected allergen. These adverse events frequently include a local reaction at the site of allergen injection, but also life-threatening systemic reactions such as asthma and anaphylaxis. This is why the administered allergen doses must be kept relatively low, which unfortunately favours Th2 immune responses in contrast to higher doses [3][4][5].Several strategies have been developed to tackle the problems of SIT, i.e. to reduce its side effects and to enhance its immunogenicity. One strategy is to replace the currently used aluminium salts, which have Th2-polarizing properties, with novel adjuvants such as Tolllike receptor ligands [6,7] that trigger Th1 responses. Another strategy is to increase safety and tolerability of SIT by injecting the allergen in a form that is not recognised by IgE, such as naked DNA vaccines Heat-denaturation is well known to reduce the reactogenicity of allergens with IgE, as cooked foods are usually well or better tolerated by allergic individuals [24][25][26]. In this study, we tested whether this very simple strate...

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Section: Discussionsupporting

confidence: 92%

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

et al. 2005

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“…Disruption or modification of the tertiary structure of allergens is an effective way to reduce the IgE-binding activity of allergens when designing safer vaccines for allergen-specific immunotherapy (17,(47)(48)(49)(50), and the change in the tertiary structure can modulate the immune response, suggesting that such modified allergens might contribute to the efficacy of the therapy (68 -70). Recently, Magi et al (69) reported immunogenic differences between a recombinant pro-Der p 1, which has an additional prodomain of 80 aa at the N-terminal of mature Der p 1 of 222 aa, and its heat-denatured form in mice. As they immunized mice with pro-Der p 1 or heat-denatured pro-Der p 1 and used pro-Der p 1 for the measurement of Ag-specific Abs and restimulation of spleen cells, the humoral and cellular responses potentially include responses against the prodomain, which composes approximately one-fourth of pro-Der p 1.…”

Section: Discussionmentioning

confidence: 99%

Crucial Commitment of Proteolytic Activity of a Purified Recombinant Major House Dust Mite Allergen Der p1 to Sensitization toward IgE and IgG Responses

Kikuchi

Takai²,

Kuhara³

et al. 2006

The Journal of Immunology

102

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The major proteolytic allergen derived from the house dust mite Dermatophagoides pteronyssinus, Der p1, is one of the most clinically relevant allergens worldwide. In the present study, we evaluate the contribution of the proteolytic activity and structure of a highly purified rDer p 1 to immune responses. Mice were i.p. immunized with three forms of rDer p 1 adsorbed to Alum: one enzymatically active, one treated with an irreversible cysteine protease-specific inhibitor, E-64, and one heat denatured. Immunization with E-64-treated or heat-denatured rDer p 1 elicited much less production of serum total IgE and not only rDer p 1-specific IgE but also IgGs compared with immunization with active rDer p 1. Assays for Ab-binding and its inhibition and structural analyses indicated that E-64-treated rDer p 1 retained its global structure and conformational B cell epitopes. A proliferative response and production of IL-5 by spleen cells restimulated with rDer p 1 were observed on immunization with the active rDer p 1 but not E-64-treated rDer p 1. The cells from mice immunized with heat-denatured rDer p 1 exhibited the highest levels of proliferation and production of IL-5 and IFN-γ. The results indicate that the proteolytic activity of the highly purified rDer p 1 crucially commits to the sensitization process, including both IgE and IgG responses. Additionally, we demonstrated immunogenic differences by functional or structural manipulations of the rDer p 1. The findings have implications for sensitization to this relevant allergen in humans and for the design of modified allergen-vaccines for future allergen-specific immunotherapy.

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“…18 The specific anti-D pteronyssinus IgE values (ImmunoCAP; Phadia, Uppsala, Sweden) of sera from patients with mite allergy were above the upper cutoff value of 100 kU/L.…”

Section: Ige-binding Activitymentioning

confidence: 99%

A hypoallergenic variant of Der p 1 as a candidate for mite allergy vaccines

Walgraffe

Mattéotti

Bakkoury

et al. 2009

Journal of Allergy and Clinical Immunology

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Heat denaturation affects the ProDer p 1 IgE reactivity and downregulates the development of the specific allergic response☆

Cited by 19 publications

References 51 publications

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

Crucial Commitment of Proteolytic Activity of a Purified Recombinant Major House Dust Mite Allergen Der p1 to Sensitization toward IgE and IgG Responses

A hypoallergenic variant of Der p 1 as a candidate for mite allergy vaccines

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