T cell epitope-containing hypoallergenic recombinant fragments of the major birch pollen allergen, Bet v 1, induce blocking antibodies.
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-gamma 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.
Vrtala
S
S
Department of Pathophysiology, Vienna General Hospital, University of Vienna, Vienna, Austria. Swiss Institute of Allergy and Asthma Research, Davos, Switzerland.
Akdis
C A
CA
Budak
F
F
Akdis
M
M
Blaser
K
K
Kraft
D
D
Valenta
R
R
D000485:Allergens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000096:biosynthesis* / Q000378:metabolism; D052179:Antigens, Plant; D001666:Binding Sites, Antibody / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003429:Cross Reactions; D016207:Cytokines / Q000378:metabolism; D003888:Desensitization, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D010940:Plant Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011058:Pollen / Q000276:immunology; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology*; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D014197:Trees
D000485:Allergens; D019138:Antibodies, Blocking; D052179:Antigens, Plant; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D010446:Peptide Fragments; D010940:Plant Proteins; D011994:Recombinant Proteins; C061312:Bet v 1 allergen, Betula; D007073:Immunoglobulin E