Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: Results of a phase I trial

Fellrath, Jean-Marc; Kettner, Alexander; Dufour, Nathalie; Frigerio, C.; Schneeberger, Dominique; Leimgruber, A.; Corradin, Gampietro; Spertini, François

doi:10.1067/mai.2003.1337

Cited by 127 publications

(92 citation statements)

References 37 publications

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“…However, SIT is time consuming, costly and bears the risk of allergic side effects. The latter can be reduced by pretreatment with anti-histamines [27,28], or by the use of allergen-derived peptides [17][18][19], chemically modified allergens [29,30] or recombinant allergens [11][12][13]31] with a reduced capacity to bind IgE. For instance, by producing fusion proteins of major allergens, one aim was to reduce IgE binding and therefore the allergic side effects, while yet retaining the immunotherapeutic potential due to preserved T cell epitopes, changes in protein folding and relative exposure of B cell epitopes [9].…”

Section: Discussionmentioning

confidence: 99%

“…For the same reasons, short, synthetic peptide sequences corresponding to T cell epitopes from the allergen have been used for SIT. This approach was able to modify surrogate markers of allergy including cutaneous responses to allergen challenge and ex vivo parameters of T cell activation [17][18][19]. Finally, chemical crosslinking of allergens by use of bi-functional aldehydes to produce so-called allergoids [20] has been shown to reduce reactogenicity with IgE while yet improving antigen processing, Th1 cytokine secretion, and efficacy [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2005

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“…The precise molecular mechanism of antigen-mediated immune deviation is unknown but results of our earlier study with rAsp f 3 mutants showed that the immune deviation occurs in mice treated with non IgE binding deletion mutants (18). Therapy with long synthetic peptides derived from PLA2, a major bee venom allergen, was able to induce T-cell anergy, immune deviation towards Th1 type cytokine response, enhanced IL-10 secretion and PLA2 specific IgG4 production (26).…”

Section: Discussionmentioning

confidence: 96%

Immune response to n-terminal and c-terminal deletion mutants of Aspergillus fumigatus major allergen ASP F 3

Singh

Banerjee

Naik

et al. 2006

Indian J Clin Biochem

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“…Therefore, the use of synthetic peptides corresponding to MHC class II-restricted T cell epitopes not containing conformational Ab epitopes for allergens could be an effective way to avoid IgE-mediated cell activation (3). Indeed, for cat and bee venom allergies, clinical studies with therapeutic peptide vaccination have already been done and were shown to reduce sensitivity to allergens (5)(6)(7)(8)(9)(10)(11)(12)(13). Moreover, it is clear that desirable peptides for therapeutic vaccines should be promiscuous T cell epitopes, which would be recognized by CD4 ϩ T cells in the context of more than one MHC class II allele, allowing broad population coverage (3).…”

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confidence: 99%

Functional Analysis of Birch Pollen Allergen Bet v 1-Specific Regulatory T Cells

Nagato

Kobayashi

Yanai

et al. 2007

The Journal of Immunology

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Allergen-specific immunotherapy using peptides is an efficient treatment for allergic diseases. Recent studies suggest that the induction of CD4+ regulatory T (Treg) cells might be associated with the suppression of allergic responses in patients after allergen-specific immunotherapy. Our aim was to identify MHC class II promiscuous T cell epitopes for the birch pollen allergen Bet v 1 capable of stimulating Treg cells with the purpose of inhibiting allergic responses. Ag-reactive CD4+ T cell clones were generated from patients with birch pollen allergy and healthy volunteers by in vitro vaccination of PBMC using Bet v 1 synthetic peptides. Several CD4+ T cell clones were induced by using 2 synthetic peptides (Bet v 1141–156 and Bet v 151–68). Peptide-reactive CD4+ T cells recognized recombinant Bet v 1 protein, indicating that these peptides are produced by the MHC class II Ag processing pathway. Peptide Bet v 1141–156 appears to be a highly MHC promiscuous epitope since T cell responses restricted by numerous MHC class II molecules (DR4, DR9, DR11, DR15, and DR53) were observed. Two of these clones functioned as typical Treg cells (expressed CD25, GITR, and Foxp3 and suppressed the proliferation and IL-2 secretion of other CD4+ T cells). Notably, the suppressive activity of these Treg cells required cell-cell contact and was not mediated through soluble IL-10 or TGF-β. The identified promiscuous MHC class II epitope capable of inducing suppressive Treg responses may have important implication for the development of peptide-based Ag-specific immunotherapy to birch pollen allergy.

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Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: Results of a phase I trial

Cited by 127 publications

References 37 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

Immune response to n-terminal and c-terminal deletion mutants of Aspergillus fumigatus major allergen ASP F 3

Functional Analysis of Birch Pollen Allergen Bet v 1-Specific Regulatory T Cells

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