Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity.

BACKGROUND We have performed a double-blind, placebo-controlled injection immunotherapy study with genetically modified derivatives of the major birch pollen allergen, Bet v 1 (Bet v 1-trimer, Bet v 1-fragments). OBJECTIVE To investigate whether vaccination with genetically modified allergens induces allergen-specific antibodies in nasal secretions and to study whether these antibodies affect nasal allergen sensitivity. METHODS A randomly picked subgroup of patients (n = 23; placebo, n = 10; trimer, n = 10; fragments, n = 3) was subjected to an extensive analysis of serum samples and nasal lavage fluids and to nasal provocation testing. Bet v 1-specific IgG(1-4) and IgA antibodies were determined in serum samples obtained before and after vaccination, after the birch pollen season, and 1 year after start of vaccination as well as in nasal lavage fluids obtained after the birch pollen season and 1 year after start of vaccination by ELISA. Nasal sensitivity to natural, birch pollen-derived Bet v 1 was determined by active anterior rhinomanometry after the birch pollen season and 1 year after start of vaccination. RESULTS Vaccination with genetically modified Bet v 1 derivatives, but not with placebo, induced Bet v 1-specific IgG1, IgG2, and IgG4, and low IgA antibodies in serum, which also appeared in nasal secretions, but no IgG3 antibodies. The levels of therapy-induced Bet v 1-specific IgG4 antibodies in nasal secretions were significantly (P < .05) associated with reduced nasal sensitivity to natural, birch pollen-derived Bet v 1 as objectively determined by controlled nasal provocation experiments. CONCLUSION Our data demonstrate that vaccination with genetically modified allergens induces IgG antibody responses against the corresponding natural allergen not only in serum but also in mucosal fluids, where they may protect against allergen-induced inflammation.

[1]  C. Suphioglu,et al.  Hypoallergenic Variants of the Major Latex Allergen Hev b 6.01 Retaining Human T Lymphocyte Reactivity1 , 2004, The Journal of Immunology.

[2]  R. Valenta,et al.  From allergen structure to new forms of allergen-specific immunotherapy. , 2002, Current opinion in immunology.

[3]  P. Bhalla,et al.  Genetically Engineered Plant Allergens with Reduced Anaphylactic Activity , 1999, International Archives of Allergy and Immunology.

[4]  R. Valenta,et al.  Strategies for converting allergens into hypoallergenic vaccine candidates. , 2004, Methods.

[5]  K. Hoffmann‐Sommergruber,et al.  Purification and characterization of recombinant Bet v I, the major birch pollen allergen. Immunological equivalence to natural Bet v I. , 1993, The Journal of biological chemistry.

[6]  Oster,et al.  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 , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[7]  R. Valenta,et al.  Vaccines for birch pollen allergy based on genetically engineered hypoallergenic derivatives of the major birch pollen allergen, Bet v 1 , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[8]  R. Valenta,et al.  Renaissance of the Blocking Antibody Concept in Type I Allergy , 2003, International Archives of Allergy and Immunology.

[9]  H. Breiteneder,et al.  Genetic Engineering of Allergens: Future Therapeutic Products , 2002, International Archives of Allergy and Immunology.

[10]  D. Kemeny,et al.  Histamine release from peripheral blood leukocytes with purified bee venom allergens: effect of hyperimmune beekeeper plasma. , 1989, International archives of allergy and applied immunology.

[11]  P. Hufnagl,et al.  Genetic engineering of a hypoallergenic trimer of the major birch pollen allergen, Bet v 1 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  S. Durham,et al.  Local IgE production in nasal allergy. , 1997, International archives of allergy and immunology.

[13]  C. Dolecek,et al.  Immunologic characterization of purified recombinant timothy grass pollen (Phleum pratense) allergens (Phl p 1, Phl p2, Phl p 5). , 1996, The Journal of allergy and clinical immunology.

[14]  R. Valenta,et al.  Allergen‐specific immunotherapy with a monophosphoryl lipid A‐adjuvanted vaccine: reduced seasonally boosted immunoglobulin E production and inhibition of basophil histamine release by therapy‐induced blocking antibodies , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[15]  C. Akdis,et al.  T Cell Epitope-Containing Hypoallergenic Recombinant Fragments of the Major Birch Pollen Allergen, Bet v 1, Induce Blocking Antibodies1 , 2000, The Journal of Immunology.

[16]  R. Valenta,et al.  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. , 1997, The Journal of clinical investigation.

[17]  S. Durham,et al.  Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[18]  R. Valenta.  The future of antigen-specific immunotherapy of allergy , 2002, Nature Reviews Immunology.

[19]  S. Durham,et al.  Mechanisms of immunotherapy: IgG revisited , 2004, Current opinion in allergy and clinical immunology.

[20]  K. Hoffmann‐Sommergruber,et al.  Detection of allergen‐specific IgE in tears of grass pollen‐allergic patients with allergic rhinoconjunctivitis , 1996, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[21]  R. Valenta,et al.  Dissociation of allergen-specific IgE and IgA responses in sera and tears of pollen-allergic patients: a study performed with purified recombinant pollen allergens. , 2000, The Journal of allergy and clinical immunology.

[22]  J. Lidholm,et al.  Induction of antibody responses to new B cell epitopes indicates vaccination character of allergen immunotherapy , 1999, European journal of immunology.

[23]  C. L. Hardy,et al.  Blocking antibodies in allergen immunotherapy: the Yin and Yang , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[24]  J. Banchereau,et al.  Molecular characterization of human IgG monoclonal antibodies specific for the major birch pollen allergen Bet v 1. Anti‐allergen IgG can enhance the anaphylactic reaction , 2000, FEBS letters.

[25]  Wayne Thomas,et al.  Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.