Comparison of genetically engineered hypoallergenic rBet v 1 derivatives with rBet v 1 wild‐type by skin prick and intradermal testing: results obtained in a French population

Pauli, G.; Purohit, Ashok; Oster, J.P.; Blay, F. De; Vrtala, Susanne; Niederberger, Verena; Kraft, Dietrich; Valenta, Rudolf

doi:10.1046/j.1365-2222.2000.00869.x

Cited by 84 publications

(62 citation statements)

References 32 publications

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“…Recently we produced by genetic engineering two recombinant fragments of Bet v 1 comprising aa 1-74 and aa 75-160 (26). The recombinant Bet v 1 fragments had lost their IgE binding capacity due to lack of their conformation and thus exhibited a Ͼ100-fold reduced allergenic activity when tested for their ability to elicit immediate skin reactions in patients (26,28,29). Although T cell epitopes of several Bet v 1-specific T cell clones seemed to be present on the rBet v 1 fragments (26), no information was available as to whether the derivatives would be capable of inducing significant lymphoproliferative responses in birch pollen-allergic patients.…”

Section: Discussionmentioning

confidence: 99%

“…When we engineered two rBet v 1 fragments comprising aa 1-74 and aa 75-160, we found that the fragments, despite comprising the full Bet v 1 sequence, lacked IgE binding capacity due to a loss of their fold but induced proliferation of rBet v 1-specific T cell clones (26). Moreover, rBet v 1 fragments had a Ͼ100-fold reduced capacity to induce basophil histamine release and immediate type skin reactions in birch pollen allergic patients (26,28,29). Both rBet v 1 fragments also failed to induce eosinophil activation and late reactions in skin blisters of birch pollen-allergic patients (30).…”

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confidence: 99%

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T Cell Epitope-Containing Hypoallergenic Recombinant Fragments of the Major Birch Pollen Allergen, Bet v 1, Induce Blocking Antibodies

Vrtala

Akdiş²,

Budak³

et al. 2000

The Journal of Immunology

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Allergen-specific immunotherapy represents one of the few curative approaches toward type I allergy. Up to 25% of allergic patients are sensitized against the major birch pollen allergen, Bet v 1. By genetic engineering we produced two recombinant (r) Bet v 1 fragments comprising aa 1–74 and aa 75–160 of Bet v 1, which, due to a loss of their native-like fold, failed to bind IgE Abs and had reduced allergenic activity. Here we show that both fragments covering the full Bet v 1 sequence induced human lymphoproliferative responses similar to rBet v 1 wild type. The C-terminal rBet v 1 fragment induced higher lymphoproliferative responses than the N-terminal fragment and represented a Th1-stimulating segment with high IFN-γ production, whereas the N-terminal fragment induced higher IL-4, IL-5, and IL-13 secretion. Immunization of mice and rabbits with rBet v 1 fragments induced IgG Abs, which cross-reacted with complete Bet v 1 and Bet v 1-related plant allergens and strongly inhibited the IgE binding of allergic patients to these allergens. Thus, our results demonstrate that hypoallergenic T cell epitope-containing rBet v 1 fragments, despite lacking IgE epitopes, can induce Abs in vivo that prevent the IgE binding of allergic patients to the wild-type allergen. The overall demonstration of the immunogenic features of the hypoallergenic rBet v 1 fragments will now enable clinical studies for safer and more efficient specific immunotherapy.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

T Cell Epitope-Containing Hypoallergenic Recombinant Fragments of the Major Birch Pollen Allergen, Bet v 1, Induce Blocking Antibodies

Vrtala

Akdiş²,

Budak³

et al. 2000

The Journal of Immunology

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“…Patients received typically eight s.c. injections containing increasing doses (1,2,4,8,10,20,40, and 80 g of protein) of the trial preparations or placebo in one to two weekly intervals as a preseasonal treatment. Because of the strongly reduced allergenic activity of the recombinant allergen derivatives (16,17), maximal doses of 80 g of the active preparations per injection were tolerated by most of the patients. After reaching the maximal dose, the treatment was continued at four weekly intervals until the beginning of the flowering season.…”

Section: Methodsmentioning

confidence: 99%

Vaccination with genetically engineered allergens prevents progression of allergic disease

Niederberger

Horak

Vrtala

et al. 2004

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

331

316

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IgE-mediated allergy affects >25% of the population in industrialized countries. Repeated contact with the disease-eliciting allergens induces rises of allergen-specific IgE Abs and progression of the disease to more severe manifestations. Our study uses a type of vaccine that is based on genetically modified allergen derivatives to treat allergic patients. We developed hypoallergenic derivatives of the major birch pollen allergen, Bet v 1, by genetic engineering and vaccinated birch pollen-allergic patients (n ‫؍‬ 124) in a double-blind, placebo-controlled study. Active treatment induced protective IgG Abs that inhibited allergen-induced release of inflammatory mediators. We also observed a reduction of cutaneous sensitivity as well as an improvement of symptoms in actively treated patients. Most important, rises of allergen-specific IgE induced by seasonal birch pollen exposure were significantly reduced in vaccinated patients. Vaccination with genetically engineered allergen derivatives is a therapy for allergy that not only ameliorates allergic reactions but also reduces the IgE production underlying the disease.

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“…In general, allergoids have demonstrated efficacy and safety profiles similar to those described for unmodified allergen extracts (90). In other studies, the introduction of point mutations or deletions has been used to reduce the number of conformational B cell epitopes displayed by an allergen (91). More recently, allergen has been coupled to synthetic bacterial DNA sequences (92).…”

Section: Figurementioning

confidence: 99%

Tregs and allergic disease

Robinson¹,

Larché²,

Durham³

2004

J. Clin. Invest.

262

176

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Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect up to 15% of populations in Westernized countries. The description of Tregs as T cells that prevent development of autoimmune disease led to considerable interest in whether these Tregs were also normally involved in prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for the therapy of allergic disease. Current data suggest that Th2 responses to allergens are normally suppressed by both CD4 + CD25 + Tregs and IL-10 Tregs. Furthermore, suppression by these subsets is decreased in allergic individuals. In animal models, Tregs could be induced by high-or low-dose inhaled antigen, and prior induction of such Tregs prevented subsequent development of allergen sensitization and airway inflammation in inhaled challenge models. For many years, allergen-injection immunotherapy has been used for the therapy of allergic disease, and this treatment may induce IL-10 Tregs, leading to both suppression of Th2 responses and a switch from IgE to IgG4 antibody production. Improvements in allergen immunotherapy, such as peptide therapy, and greater understanding of the biology of Tregs hold great promise for the treatment and prevention of allergic disease.

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Comparison of genetically engineered hypoallergenic rBet v 1 derivatives with rBet v 1 wild‐type by skin prick and intradermal testing: results obtained in a French population

Abstract: Genetically modified hypoallergenic derivatives of the major birch pollen allergen, Bet v 1 showed reduced capacity to induce immediate type skin reactions. They may represent candidate molecules for immunotherapy of birch pollen allergy with reduced risk of anaphylactic side-effects.

Cited by 84 publications

References 32 publications

T Cell Epitope-Containing Hypoallergenic Recombinant Fragments of the Major Birch Pollen Allergen, Bet v 1, Induce Blocking Antibodies

T Cell Epitope-Containing Hypoallergenic Recombinant Fragments of the Major Birch Pollen Allergen, Bet v 1, Induce Blocking Antibodies

Vaccination with genetically engineered allergens prevents progression of allergic disease

Tregs and allergic disease

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