From allergen genes to new forms of allergy diagnosis and treatment

Allergy: European Journal of Allergy and Clinical Immunology

Volumn 63, Issue 3, 2008, Pages 299-309

  Vrtala, S ^a  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

Author keywords

Allergy; Diagnosis; Hypoallergenic derivatives; Immunotherapy; Recombinant allergens

Indexed keywords

ALLERGEN; GRASS POLLEN EXTRACT; HOUSE DUST ALLERGEN; HYPOALLERGENIC ALLERGEN; IMMUNOGLOBULIN E; RECOMBINANT ALLERGEN; TROPOMYOSIN; UNCLASSIFIED DRUG;

ALLERGIC REACTION; ALLERGY; DIAGNOSTIC PROCEDURE; DIAGNOSTIC TEST; DRUG MECHANISM; ENZYME ACTIVITY; GENE; HUMAN; IMMUNOGENICITY; IMMUNOGOLD ELECTRON MICROSCOPY; IMMUNOMODULATION; IMMUNOTHERAPY; LYMPHOPROLIFERATIVE DISEASE; MOLECULAR BIOLOGY; PHLEUM PRATENSE; PRIORITY JOURNAL; REVIEW; SENSITIZATION; TREATMENT INDICATION; TYPE I ALLERGY;

ALLERGENS; ANTI-ALLERGIC AGENTS; CLINICAL TRIALS AS TOPIC; COMBINED MODALITY THERAPY; FEMALE; FORECASTING; HUMANS; HYPERSENSITIVITY; IMMUNOTHERAPY; MALE; PROGNOSIS; RECOMBINANT PROTEINS; RISK ASSESSMENT; SKIN TESTS; TREATMENT OUTCOME;

EID: 38949120490     PISSN: 01054538     EISSN: 13989995     Source Type: Journal    
DOI: 10.1111/j.1398-9995.2007.01609.x     Document Type: Review

References (100)

1. Neukirch F, Pin I, Knani J, Henry C, Pison C, Liard R et al. Prevalence of asthma and asthma-like symptoms in three French cities. Respir Med 1995 89 : 685 692.
2. Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 2001 1 : 69 75.
3. Kinet JP. The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. Annu Rev Immunol 1999 17 : 931 972.
4. Schroeder JT, MacGlashan DW Jr., Lichtenstein LM. Human basophils: mediator release and cytokine production. Adv Immunol 2001 77 : 93 122.
5. Turner H, Kinet JP. Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature 1999 402 (Suppl. 6760 B24 B30.
6. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998 102 : 558 562.
7. Ebner C, Siemann U, Bohle B, Willheim M, Wiedermann U, Schenk S et al. Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clin Exp Allergy 1997 27 : 1007 1015.
8. Secrist H, Chelen CJ, Wen Y, Marshall JD, Umetsu DT. Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J Exp Med 1993 178 : 2123 2130.
9. Larche M. Immunoregulation by targeting T cells in the treatment of allergy and asthma. Curr Opin Immunol 2006 18 : 745 750.
10. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 2004 199 : 1567 1575.
11. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 2007 119 : 780 791.
12. Jutel M, Akdis M, Blaser K, Akdis CA. Mechanisms of allergen specific immunotherapy - T-cell tolerance and more. Allergy 2006 61 : 796 807.
13. Mothes N, Heinzkill M, Drachenberg KJ, Sperr WR, Krauth MT, Majlesi Y 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. Clin Exp Allergy 2003 33 : 1198 1208.
14. Reisinger J, Horak F, Pauli G, Van Hage M, Cromwell O, Konig F et al. Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity. J Allergy Clin Immunol 2005 116 : 347 354.
15. Niederberger V, Horak F, Vrtala S, Spitzauer S, Krauth MT, Valent P et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci USA 2004 101 (Suppl. 2 14677 14682.
16. Moverare R, Elfman L, Vesterinen E, Metso T, Haahtela T. Development of new IgE specificities to allergenic components in birch pollen extract during specific immunotherapy studied with immunoblotting and Pharmacia CAP System. Allergy 2002 57 : 423 430.
17. Van Hage-Hamsten M, Valenta R. Specific immunotherapy - the induction of new IgE-specificities? Allergy 2002 57 : 375 378.
18. Mellerup MT, Hahn GW, Poulsen LK, Malling H. Safety of allergen-specific immunotherapy. Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment. Clin Exp Allergy 2000 30 : 1423 1429.
19. Marsh DG, Lichtenstein LM, Campbell DH. Studies on 'allergoids' prepared from naturally occurring allergens. I. Assay of allergenicity and antigenicity of formalinized rye group I component. Immunology 1970 18 : 705 722.
20. Marsh DG, Norman PS, Roebber M, Lichtenstein LM. Studies on allergoids from naturally occurring allergens. III. Preparation of ragweed pollen allergoids by aldehyde modification in two steps. J Allergy Clin Immunol 1981 68 : 449 459.
21. King TP, Kochoumian L, Chiorazzi N. Immunological properties of conjugates of ragweed pollen antigen E with methoxypolyethylene glycol or a copolymer of D-glutamic acid and D-lysine. J Exp Med 1979 149 : 424 435.
22. Maasch HJ, Marsh DG. Standardized extracts modified allergens - allergoids. Clin Rev Allergy 1987 5 : 89 106.
23. Thomas WR, Stewart GA, Simpson RJ, Chua KY, Plozza TM, Dilworth RJ et al. Cloning and expression of DNA coding for the major house dust mite allergen Der p 1 in Escherichia coli. Int Arch Allergy Appl Immunol 1988 85 : 127 129.
24. Valenta R, Duchene M, Vrtala S, Birkner T, Ebner C, Hirschwehr R et al. Recombinant allergens for immunoblot diagnosis of tree-pollen allergy. J Allergy Clin Immunol 1991 88 : 889 894.
25. Valenta R, Vrtala S, Ebner C, Kraft D, Scheiner O. Diagnosis of grass pollen allergy with recombinant timothy grass (Phleum pratense) pollen allergens. Int Arch Allergy Immunol 1992 97 : 287 294.
26. Suphioglu C. What are the important allergens in grass pollen that are linked to human allergic disease? Clin Exp Allergy 2000 30 : 1335 1341.
27. Laffer S, Valenta R, Vrtala S, Susani M, Van Ree R, Kraft D et al. Complementary DNA cloning of the major allergen Phl p I from timothy grass (Phleum pratense); recombinant Phl p I inhibits IgE binding to group I allergens from eight different grass species. J Allergy Clin Immunol 1994 94 : 689 698.
28. Dolecek C, Vrtala S, Laffer S, Steinberger P, Kraft D, Scheiner O et al. Molecular characterization of Phl p II, a major timothy grass (Phleum pratense) pollen allergen. FEBS Lett 1993 335 : 299 304.
29. Vrtala S, Sperr WR, Reimitzer I, Van Ree R, Laffer S, Muller WD et al. cDNA cloning of a major allergen from timothy grass (Phleum pratense) pollen; characterization of the recombinant Phl pV allergen. J Immunol 1993 151 : 4773 4781.
30. Vrtala S, Fischer S, Grote M, Vangelista L, Pastore A, Sperr WR et al. Molecular, immunological, and structural characterization of Phl p 6, a major allergen and P-particle-associated protein from Timothy grass (Phleum pratense) pollen. J Immunol 1999 163 : 5489 5496.
31. Niederberger V, Hayek B, Vrtala S, Laffer S, Twardosz A, Vangelista L et al. Calcium-dependent immunoglobulin E recognition of the apo- and calcium-bound form of a cross-reactive two EF-hand timothy grass pollen allergen, Phl p 7. FASEB J 1999 13 : 843 856.
32. Valenta R, Ball T, Vrtala S, Duchene M, Kraft D, Scheiner O. cDNA cloning and expression of timothy grass (Phleum pratense) pollen profilin in Escherichia coli: comparison with birch pollen profilin. Biochem Biophys Res Commun 1994 199 : 106 118.
33. Vrtala S, Wiedemann P, Mittermann I, Eichler HG, Sperr WR, Valent P et al. High-level expression in Escherichia coli and purification of recombinant plant profilins: comparison of IgE-binding capacity and allergenic activity. Biochem Biophys Res Commun 1996 226 : 42 50.
34. Valenta R, Vrtala S, Laffer S, Spitzauer S, Kraft D. Recombinant allergens. Allergy 1998 53 : 552 561.
35. Laffer S, Spitzauer S, Susani M, Pairleitner H, Schweiger C, Gronlund H et al. Comparison of recombinant timothy grass pollen allergens with natural extract for diagnosis of grass pollen allergy in different populations. J Allergy Clin Immunol 1996 98 : 652 658.
36. Niederberger V, Laffer S, Froschl R, Kraft D, Rumpold H, Kapiotis S et al. IgE antibodies to recombinant pollen allergens (Phl p 1, Phl p 2, Phl p 5, and Bet v 2) account for a high percentage of grass pollen-specific IgE. J Allergy Clin Immunol 1998 101 : 258 264.
37. Gehlhar K, Petersen A, Schramm G, Becker WM, Schlaak M, Bufe A. Investigation of different recombinant isoforms of grass group-V allergens (timothy grass pollen) isolated by low-stringency cDNA hybridization - antibody binding capacity and allergenic activity. Eur J Biochem 1997 247 : 217 223.
38. Vrtala S, Focke M, Kopec J, Verdino P, Hartl A, Sperr WR et al. Genetic engineering of the major timothy grass pollen allergen, Phl p 6, to reduce allergenic activity and preserve immunogenicity. J Immunol 2007 179 : 1730 1739.
39. Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 2005 116 : 608 613.
40. Tovey ER, Chapman MD, Platts-Mills TA. Mite faeces are a major source of house dust allergens. Nature 1981 289 : 592 593.
41. Thomas WR, Smith WA, Hales BJ, Mills KL, O'Brien RM. Characterization and immunobiology of house dust mite allergens. Int Arch Allergy Immunol 2002 129 : 1 18.
42. Thomas WR, Smith W. Towards defining the full spectrum of important house dust mite allergens. Clin Exp Allergy 1999 29 : 1583 1587.
43. Weghofer M, Thomas WR, Pittner G, Horak F, Valenta R, Vrtala S. Comparison of purified Dermatophagoides pteronyssinus allergens and extract by two-dimensional immunoblotting and quantitative immunoglobulin E inhibitions. Clin Exp Allergy 2005 35 : 1384 1391.
44. Westritschnig K, Sibanda E, Thomas W, Auer H, Aspock H, Pittner G et al. Analysis of the sensitization profile towards allergens in central Africa. Clin Exp Allergy 2003 33 : 22 27.
45. Hiller R, Laffer S, Harwanegg C, Huber M, Schmidt WM, Twardosz A et al. Microarrayed allergen molecules: diagnostic gatekeepers for allergy treatment. FASEB J 2002 16 : 414 416.
46. Pittner G, Vrtala S, Thomas WR, Weghofer M, Kundi M, Horak F et al. Component-resolved diagnosis of house-dust mite allergy with purified natural and recombinant mite allergens. Clin Exp Allergy 2004 34 : 597 603.
47. Valenta R, Lidholm J, Niederberger V, Hayek B, Kraft D, Gronlund H. The recombinant allergen-based concept of component-resolved diagnostics and immunotherapy (CRD and CRIT). Clin Exp Allergy 1999 29 : 896 904.
48. Valenta R, Vrtala S, Focke-Tejkl M, Bugajska S, Ball T, Twardosz A et al. Genetically engineered and synthetic allergen derivatives: candidates for vaccination against type I allergy. Biol Chem 1999 380 : 815 824.
49. Van Ree R, Antonicelli L, Akkerdaas JH, Garritani MS, Aalberse RC, Bonifazi F. Possible induction of food allergy during mite immunotherapy. Allergy 1996 51 : 108 113.
50. Vrtala S, Grote M, Duchene M, Van Ree R, Kraft D, Scheiner O et al. Properties of tree and grass pollen allergens: reinvestigation of the linkage between solubility and allergenicity. Int Arch Allergy Immunol 1993 102 : 160 169.
51. Bufe A. The biological function of allergens: relevant for the induction of allergic diseases? Int Arch Allergy Immunol 1998 117 : 215 219.
52. Grote M, Vrtala S, Niederberger V, Valenta R, Reichelt R. Expulsion of allergen-containing materials from hydrated rye grass (Lolium perenne) pollen revealed by using immunogold field emission scanning and transmission electron microscopy. J Allergy Clin Immunol 2000 105 : 1140 1145.
53. Grote M, Vrtala S, Niederberger V, Wiermann R, Valenta R, Reichelt R. Release of allergen-bearing cytoplasm from hydrated pollen: a mechanism common to a variety of grass (Poaceae) species revealed by electron microscopy. J Allergy Clin Immunol 2001 108 : 109 115.
54. Suphioglu C, Singh MB, Taylor P, Bellomo R, Holmes P, Puy R et al. Mechanism of grass-pollen-induced asthma. Lancet 1992 339 : 569 572.
55. Park GM, Lee SM, Lee IY, Ree HI, Kim KS, Hong CS et al. Localization of a major allergen, Der p 2, in the gut and faecal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy 2000 30 : 1293 1297.
56. Stern DA, Riedler J, Nowak D, Braun-Fahrlander C, Swoboda I, Balic N et al. Exposure to a farming environment has allergen-specific protective effects on TH2-dependent isotype switching in response to common inhalants. J Allergy Clin Immunol 2007 119 : 351 358.
57. Vrtala S, Ball T, Spitzauer S, Pandjaitan B, Suphioglu C, Knox B et al. Immunization with purified natural and recombinant allergens induces mouse IgG1 antibodies that recognize similar epitopes as human IgE and inhibit the human IgE-allergen interaction and allergen-induced basophil degranulation. J Immunol 1998 160 : 6137 6144.
58. Vrtala S, Mayer P, Ferreira F, Susani M, Sehon AH, Kraft D et al. Induction of IgE antibodies in mice and rhesus monkeys with recombinant birch pollen allergens: different allergenicity of Bet v 1 and Bet v 2. J Allergy Clin Immunol 1996 98 : 913 921.
59. Maglio O, Saldanha JW, Vrtala S, Spitzauer S, Valenta R, Pastore A. A major IgE epitope-containing grass pollen allergen domain from Phl p 5 folds as a four-helix bundle. Protein Eng 2002 15 : 635 642.
60. De Marino S, Morelli MA, Fraternali F, Tamborini E, Musco G, Vrtala S et al. An immunoglobulin-like fold in a major plant allergen: the solution structure of Phl p 2 from timothy grass pollen. Structure Fold Des 1999 7 : 943 952.
61. Vrtala S, Focke-Tejkl M, Swoboda I, Kraft D, Valenta R. Strategies for converting allergens into hypoallergenic vaccine candidates. Methods 2004 32 : 313 320.
62. Vrtala S, Hirtenlehner K, Vangelista L, Pastore A, Eichler HG, Sperr WR 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. J Clin Invest 1997 99 : 1673 1681.
63. Zeiler T, Taivainen A, Rytkonen M, Rautiainen J, Karjalainen H, Mantyjarvi R et al. Recombinant allergen fragments as candidate preparations for allergen immunotherapy. J Allergy Clin Immunol 1997 100 : 721 727.
64. Pace E, Duro G, La Grutta S, Ferraro M, Bruno A, Bousquet J et al. Hypoallergenic fragment of Par j 2 increases functional expression of Toll-like receptors in atopic children. Allergy 2006 61 : 1459 1466.
65. Vrtala S, Hirtenlehner K, Susani M, Akdis M, Kussebi F, Akdis CA et al. Genetic engineering of a hypoallergenic trimer of the major birch pollen allergen Bet v 1. FASEB J 2001 15 : 2045 2047.
66. King TP, Jim SY, Monsalve RI, Kagey-Sobotka A, Lichtenstein LM, Spangfort MD. Recombinant allergens with reduced allergenicity but retaining immunogenicity of the natural allergens: hybrids of yellow jacket and paper wasp venom allergen antigen 5s. J Immunol 2001 166 : 6057 6065.
67. Schramm G, Kahlert H, Suck R, Weber B, Stuwe HT, Muller WD et al. 'Allergen engineering': variants of the timothy grass pollen allergen Phl p 5b with reduced IgE-binding capacity but conserved T cell reactivity. J Immunol 1999 162 : 2406 2414.
68. Ferreira F, Ebner C, Kramer B, Casari G, Briza P, Kungl AJ et al. Modulation of IgE reactivity of allergens by site-directed mutagenesis: potential use of hypoallergenic variants for immunotherapy. FASEB J 1998 12 : 231 242.
69. Okada T, Swoboda I, Bhalla PL, Toriyama K, Singh MB. Engineering of hypoallergenic mutants of the Brassica pollen allergen, Bra r 1, for immunotherapy. FEBS Lett 1998 434 : 255 260.
70. Swoboda I, De Weerd N, Bhalla PL, Niederberger V, Sperr WR, Valent P et al. Mutants of the major ryegrass pollen allergen, Lol p 5, with reduced IgE-binding capacity: candidates for grass pollen-specific immunotherapy. Eur J Immunol 2002 32 : 270 280.
71. Smith AM, Chapman MD. Reduction in IgE binding to allergen variants generated by site-directed mutagenesis: contribution of disulfide bonds to the antigenic structure of the major house dust mite allergen Der p 2. Mol Immunol 1996 33 : 399 405.
72. Tighe H, Takabayashi K, Schwartz D, Van Nest G, Tuck S, Eiden JJ et al. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy Clin Immunol 2000 106 : 124 134.
73. Spiegelberg HL, Horner AA, Takabayashi K, Raz E. Allergen- immunostimulatory oligodeoxynucleotide conjugate: a novel allergoid for immunotherapy. Curr Opin Allergy Clin Immunol 2002 2 : 547 551.
74. Muller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F et al. Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J Allergy Clin Immunol 1998 101 : 747 754.
75. Oldfield WL, Larche M, Kay AB. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial. Lancet 2002 360 : 47 53.
76. Focke M, Mahler V, Ball T, Sperr WR, Majlesi Y, Valent P et al. Nonanaphylactic synthetic peptides derived from B cell epitopes of the major grass pollen allergen, Phl p 1, for allergy vaccination. FASEB J 2001 15 : 2042 2044.
77. Focke M, Linhart B, Hartl A, Wiedermann U, Sperr WR, Valent P et al. Non-anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v 1, for preventive vaccination. Clin Exp Allergy 2004 34 : 1525 1533.
78. Jung K, Schlenvoigt G, Jager L. Allergologic-immunochemical study of tree and bush pollen. III - Cross reactions of human IgE antibodies with various tree pollen allergens. Allergy Immunol (Leipz) 1987 33 : 223 230.
79. Halmepuro L, Vuontela K, Kalimo K, Bjorksten F. Cross-reactivity of IgE antibodies with allergens in birch pollen, fruits and vegetables. Int Arch Allergy Appl Immunol 1984 74 : 235 240.
80. Jarolim E, Rumpold H, Endler AT, Ebner H, Breitenbach M, Scheiner O et al. IgE and IgG antibodies of patients with allergy to birch pollen as tools to define the allergen profile of Betula verrucosa. Allergy 1989 44 : 385 395.
81. Ipsen H, Lowenstein H. Isolation and immunochemical characterization of the major allergen of birch pollen (Betula verrucosa). J Allergy Clin Immunol 1983 72 : 150 159.
82. Kazemi-Shirazi L, Pauli G, Purohit A, Spitzauer S, Froschl R, Hoffmann-Sommergruber K et al. Quantitative IgE inhibition experiments with purified recombinant allergens indicate pollen-derived allergens as the sensitizing agents responsible for many forms of plant food allergy. J Allergy Clin Immunol 2000 105 : 116 125.
83. Vrtala S, Hirtenlehner K, Vangelista L, Pastore A, Eichler HG, Sperr WR et al. Division of the major birch pollen allergen, Bet v 1, into two non-anaphylactic fragments. Int Arch Allergy Immunol 1997 113 : 246 248.
84. Vrtala S, Hirtenlehner K, Susani M, Hufnagl P, Binder BR, Vangelista L et al. Genetic engineering of recombinant hypoallergenic oligomers of the major birch pollen allergen, Bet v 1: candidates for specific immunotherapy. Int Arch Allergy Immunol 1999 118 : 218 219.
85. Vrtala S, Akdis CA, Budak F, Akdis M, Blaser K, Kraft D et al. T cell epitope-containing hypoallergenic recombinant fragments of the major birch pollen allergen, Bet v 1, induce blocking antibodies. J Immunol 2000 165 : 6653 6659.
86. Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol 2004 172 : 3252 3259.
87. Flicker S, Valenta R. Renaissance of the blocking antibody concept in type I allergy. Int Arch Allergy Immunol 2003 132 : 13 24.
88. Horner AA, Takabayashi K, Beck L, Sharma B, Zubeldia J, Baird S et al. Optimized conjugation ratios lead to allergen immunostimulatory oligodeoxynucleotide conjugates with retained immunogenicity and minimal anaphylactogenicity. J Allergy Clin Immunol 2002 110 : 413 420.
89. Mahler V, Vrtala S, Kuss O, Diepgen TL, Suck R, Cromwell O et al. Vaccines for birch pollen allergy based on genetically engineered hypoallergenic derivatives of the major birch pollen allergen, Bet v 1. Clin Exp Allergy 2004 34 : 115 122.
90. Van Hage-Hamsten M, Kronqvist M, Zetterstrom O, Johansson E, Niederberger V, Vrtala S et al. Skin test evaluation of genetically engineered hypoallergenic derivatives of the major birch pollen allergen, Bet v 1: results obtained with a mix of two recombinant Bet v 1 fragments and recombinant Bet v 1 trimer in a Swedish population before the birch pollen season. J Allergy Clin Immunol 1999 104 : 969 977.
91. Pauli G, Purohit A, Oster JP, De Blay F, Vrtala S, Niederberger V 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. Clin Exp Allergy 2000 30 : 1076 1084.
92. Pauli G, Purohit A, Oster JP, De Blay F, Vrtala S, Niederberger V et al. Clinical evaluation of genetically engineered hypoallergenic rBet v 1 derivatives. Int Arch Allergy Immunol 1999 118 : 216 217.
93. Nopp A, Hallden G, Lundahl J, Johansson E, Vrtala S, Valenta R et al. Comparison of inflammatory responses to genetically engineered hypoallergenic derivatives of the major birch pollen allergen bet v 1 and to recombinant bet v 1 wild type in skin chamber fluids collected from birch pollen-allergic patients. J Allergy Clin Immunol 2000 106 : 101 109.
94. Haselden BM, Kay AB, Larche M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med 1999 189 : 1885 1894.
95. Maguire P, Nicodemus C, Robinson D, Aaronson D, Umetsu DT. The safety and efficacy of ALLERVAX CAT in cat allergic patients. Clin Immunol 1999 93 : 222 231.
96. Oldfield WL, Kay AB, Larche M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects. J Immunol 2001 167 : 1734 1739.
97. Gafvelin G, Thunberg S, Kronqvist M, Gronlund H, Gronneberg R, Troye-Blomberg M et al. Cytokine and antibody responses in birch-pollen-allergic patients treated with genetically modified derivatives of the major birch pollen allergen Bet v 1. Int Arch Allergy Immunol 2005 138 : 59 66.
98. Boulet LP, Turcotte H, Laprise C, Lavertu C, Bedard PM, Lavoie A et al. Comparative degree and type of sensitization to common indoor and outdoor allergens in subjects with allergic rhinitis and/or asthma. Clin Exp Allergy 1997 27 : 52 59.
99. Linhart B, Hartl A, Jahn-Schmid B, Verdino P, Keller W, Krauth MT et al. A hybrid molecule resembling the epitope spectrum of grass pollen for allergy vaccination. J Allergy Clin Immunol 2005 115 : 1010 1016.
100. Linhart B, Jahn-Schmid B, Verdino P, Keller W, Ebner C, Kraft D et al. Combination vaccines for the treatment of grass pollen allergy consisting of genetically engineered hybrid molecules with increased immunogenicity. FASEB J 2002 16 : 1301 1303.