Conversion of the major birch pollen allergen, Bet v 1, into two nonanaphylactic T cell epitope-containing fragments: candidates for a novel form of specific immunotherapy.

Vrtala, Susanne; Hirtenlehner, Kora; Vangelista, Luca; Pastore, Annalisa; Eichler, Hans Georg; Sperr, Wolfgang R.; Valent, Peter; Ebner, Christof; Kraft, Dietrich; Valenta, Rudolf

doi:10.1172/jci119330

Cited by 199 publications

(235 citation statements)

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“…Folded rBet v 1a, which had been expressed in E. coli and purified as described (31), was obtained from Biomay (Linz, Austria). rBet v 1 fragments, comprising aa 1-74 and aa 75-160, were generated by PCR, using the rBet v 1a cDNA as a template, subcloned into plasmid pET-17b, expressed in E. coli strain BL 21 (DE3), and purified as described (26).…”

Section: Patients' Sera Plasmid Vectors E Coli Strains and Recombmentioning

confidence: 99%

“…The cDNA coding for Bet v 1 was isolated (19), and recombinant Bet v 1, which has immunological and biological properties comparable to natural Bet v 1 (18,20) and shares epitopes with homologous proteins present in the pollen of trees of the order Fagales and in plant-derived food was produced in Escherichia coli (21)(22)(23)(24). When analyzed by circular dichroism spectroscopy, the bacterially expressed rBet v 1 wild-type molecule was folded and consisted of mixed ␣ helical and ␤-sheet conformation (25,26). The three-dimensional structure of rBet v 1 was determined by x-ray crystallography and nuclear magnetic resonance analysis (27).…”

mentioning

confidence: 99%

“…The fact that natural and recombinant Bet v 1 fragments failed to bind IgE Abs indicated that IgE epitopes of Bet v 1 belong to the conformational (discontinuous) type (26). 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).…”

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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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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: Patients' Sera Plasmid Vectors E Coli Strains and Recombmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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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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“…Structural integrity or conformation of a number of aeroallergens seems to be important for the binding of the human IgE antibodies that initiate allergic reactions (Lombardero et al, 1990;Vrtala et al, 1997). Grass pollen allergen Phl p 5b (Schramm et al, 2001), mite allergen Der f 2 (Takai et al, 1997) and cherry allergen Pru av 1 (Neudecker et al, 2003) lose their allergenic activities when they are denatured.…”

Section: Introductionmentioning

confidence: 99%

Major mountain cedar allergen, Jun a 1, contains conformational as well as linear IgE epitopes

Varshney

Goldblum

Kearney

et al. 2007

Molecular Immunology

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Induction of antibody responses to new B cell epitopes indicates vaccination character of allergen immunotherapy

et al. 1999

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Whether the modulation of antibody responses can contribute to the improvement of clinical symptoms in patients receiving allergen immunotherapy represents a controversial issue. We have used purified [seven recombinant (r) and one natural] timothy grasspollen allergens as well as recombinant B cell epitope‐containing fragments of the major timothy grass pollen allergen, Phl p 1, to investigate humoral immune responses in eight allergic patients receiving grass pollen‐specific immunotherapy. We found that the administration of aluminium hydroxide‐adsorbed grass pollen extract induced complex changes in allergen / epitope‐specific antibody responses: increases in IgG subclass (IgG1, IgG2, IgG4) responses against allergens recognized before the therapy were observed. All eight patients started to mount IgE and IgG4 responses to continuous Phl p 1 epitopes not recognized before the therapy and a de novo induction of IgE antibodies against new allergens was found in one patient. Evidence for a protective role of IgG antibodies specific for continuous Phl p 1 epitopes was provided by the demonstration that preincubation of rPhl p 1 with human serum containing therapy‐induced Phl p 1‐specific IgG inhibited rPhl p 1‐induced histamine release from basophils of a grass pollen‐allergic patient. Our finding that immunotherapy induced antibody responses against previously not recognized B cell epitopes indicates the vaccination character of this treatment. The fact that patients started to mount de novo IgE as well as protective IgG responses against epitopes may explain the unpredictability of specific immunotherapy performed with allergen extracts and emphasizes the need for novel forms of component‐resolved immunotherapy.

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Conversion of the major birch pollen allergen, Bet v 1, into two nonanaphylactic T cell epitope-containing fragments: candidates for a novel form of specific immunotherapy.

Abstract: Abstract

Cited by 199 publications

References 48 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

Major mountain cedar allergen, Jun a 1, contains conformational as well as linear IgE epitopes

Induction of antibody responses to new B cell epitopes indicates vaccination character of allergen immunotherapy

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