Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides

Clinical and Translational Allergy

François Spertini³  Christophe Reymond²  Régine Audran³  Anne-Christine Thierry³  Giampietro Corradin¹  Jacqueline Wassenberg³  Nathalie Barbier³  Caroline Boudousquié³  Yannick Perrin³  Céline Pellaton³ 

[1] Department of Biochemistry, University of Lausanne, Lausanne, Switzerland;Anergis SA, Lausanne, Switzerland;Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois (CHUV), Rue du Bugnon, 1011 Lausanne, Switzerland

关键词: Pollen;    Birch;    Immunotherapy;    Peptides;    IgE;   

Others  :  794325
DOI  :  10.1186/2045-7022-3-17

 received in 2013-02-14, accepted in 2013-05-21,  发布年份 2013

【 摘 要 】

Background

Synthetic contiguous overlapping peptides (COPs) may represent an alternative to allergen extracts or recombinant allergens for allergen specific immunotherapy. In combination, COPs encompass the entire allergen sequence, providing all potential T cell epitopes, while preventing IgE conformational epitopes of the native allergen.

Methods

Individual COPs were derived from the sequence of Bet v 1, the major allergen of birch pollen, and its known crystal structure, and designed to avoid IgE binding. Three sets of COPs were tested in vitro in competition ELISA and basophil degranulation assays. Their in vivo reactivity was determined by intraperitoneal challenge in rBet v 1 sensitized mice as well as by skin prick tests in volunteers with allergic rhinoconjunctivitis to birch pollen.

Results

The combination, named AllerT, of three COPs selected for undetectable IgE binding in competition assays and for the absence of basophil activation in vitro was unable to induce anaphylaxis in sensitized mice in contrast to rBet v 1. In addition no positive reactivity to AllerT was observed in skin prick tests in human volunteers allergic to birch pollen. In contrast, a second set of COPs, AllerT4-T5 displayed some residual IgE binding in competition ELISA and a weak subliminal reactivity to skin prick testing.

Conclusions

The hypoallergenicity of contiguous overlapping peptides was confirmed by low, if any, IgE binding activity in vitro, by the absence of basophil activation and the absence of in vivo induction of allergic reactions in mouse and human.

Trial registration

ClinicalTrials.gov NCT01719133

【 授权许可】

   
2013 Pellaton et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Spertini F, Reymond C, Leimgruber A: Allergen-specific immunotherapy of allergy and asthma: current and future trends. Expert Rev Respir Med 2009, 3:37-51.
• [2]Abramson MJ, Puy RM, Weiner JM: Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev 2010., 4(8) CD001186
• [3]Compalati E, Penagos M, Tarantini F, Passalacqua G, Canonica GW: Specific immunotherapy for respiratory allergy: state of the art according to current meta-analyses. Ann Allergy Asthma Immunol 2009, 102:22-28.
• [4]Walker SM, Durham SR, Till SJ, Roberts G, Corrigan CJ, Leech SC, Krishna MT, Rajakulasingham RK, Williams A, Chantrell J, et al.: Immunotherapy for allergic rhinitis. Clin Exp Allergy 2011, 41:1177-1200.
• [5]Winther L, Arnved J, Malling HJ, Nolte H, Mosbech H: Side-effects of allergen-specific immunotherapy: a prospective multi-centre study. Clin Exp Allergy 2006, 36:254-260.
• [6]Birnbaum J, Ramadour M, Magnan A, Vervloet D: Hymenoptera ultra-rush venom immunotherapy (210 min): a safety study and risk factors. Clin Exp Allergy 2003, 33:58-64.
• [7]Drachenberg KJ, Heinzkill M, Urban E, Woroniecki SR: Efficacy and tolerability of short-term specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A (MPL) for children and adolescents. Allergol Immunopathol (Madr) 2003, 31:270-277.
• [8]Mothes N, Heinzkill M, Drachenberg KJ, Sperr WR, Krauth MT, Majlesi Y, Semper H, Valent P, Niederberger V, Kraft D, Valenta R: 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.
• [9]DuBuske LM, Frew AJ, Horak F, Keith PK, Corrigan CJ, Aberer W, Holdich T, von Weikersthal-Drachenberg KJ: Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc 2011, 32:239-247.
• [10]Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, Li H, Coffman R, Seyfert V, Eiden JJ, Broide D: Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 2006, 355:1445-1455.
• [11]Senti G, Johansen P, Haug S, Bull C, Gottschaller C, Muller P, Pfister T, Maurer P, Bachmann MF, Graf N, Kundig TM: Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen-specific immunotherapy in humans: a phase I/IIa clinical trial. Clin Exp Allergy 2009, 39:562-570.
• [12]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.
• [13]Pauli G, Larsen TH, Rak S, Horak F, Pastorello E, Valenta R, Purohit A, Arvidsson M, Kavina A, Schroeder JW, et al.: Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J Allergy Clin Immunol 2008, 122:951-960.
• [14]Muller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, Blaser K: 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.
• [15]Niederberger V, Horak F, Vrtala S, Spitzauer S, Krauth MT, Valent P, Reisinger J, Pelzmann M, Hayek B, Kronqvist M, et al.: Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci U S A 2004, 101(Suppl 2):14677-14682.
• [16]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.
• [17]Kammerer R, Kettner A, Chvatchko Y, Dufour N, Tiercy JM, Corradin G, Spertini F: Delineation of PLA2 epitopes using short or long overlapping synthetic peptides: interest for specific immunotherapy. Clin Exp Allergy 1997, 27:1016-1026.
• [18]Kammerer R, Chvatchko Y, Kettner A, Dufour N, Corradin G, Spertini F: Modulation of T-cell response to phospholipase A2 and phospholipase A2-derived peptides by conventional bee venom immunotherapy. J Allergy Clin Immunol 1997, 100:96-103.
• [19]Swoboda I, De Weerd N, Bhalla PL, Niederberger V, Sperr WR, Valent P, Kahlert H, Fiebig H, Verdino P, Keller W, 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.
• [20]Fellrath JM, Kettner A, Dufour N, Frigerio C, Schneeberger D, Leimgruber A, Corradin G, Spertini F: Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a phase I trial. J Allergy Clin Immunol 2003, 111:854-861.
• [21]Ballmer-Weber BK, Hoffmann-Sommergruber K: Molecular diagnosis of fruit and vegetable allergy. Curr Opin Allergy Clin Immunol 2011, 11:229-235.
• [22]Bohle B: The impact of pollen-related food allergens on pollen allergy. Allergy 2007, 62:3-10.
• [23]Radauer C, Breiteneder H: Evolutionary biology of plant food allergens. J Allergy Clin Immunol 2007, 120:518-525.
• [24]Jahn-Schmid B, Radakovics A, Luttkopf D, Scheurer S, Vieths S, Ebner C, Bohle B: Bet v 1142–156 is the dominant T-cell epitope of the major birch pollen allergen and important for cross-reactivity with Bet v 1-related food allergens. J Allergy Clin Immunol 2005, 116:213-219.
• [25]Roggero MA, Servis C, Corradin G: A simple and rapid procedure for the purification of synthetic polypeptides by a combination of affinity chromatography and methionine chemistry. FEBS Lett 1997, 408:285-288.
• [26]von Garnier C, Astori M, Kettner A, Dufour N, Heusser C, Corradin G, Spertini F: Allergen-derived long peptide immunotherapy down-regulates specific IgE response and protects from anaphylaxis. Eur J Immunol 2000, 30:1638-1645.
• [27]Barbey C, Donatelli-Dufour N, Batard P, Corradin G, Spertini F: Intranasal treatment with ovalbumin but not the major T cell epitope ovalbumin 323–339 generates interleukin-10 secreting T cells and results in the induction of allergen systemic tolerance. Clin Exp Allergy 2004, 34:654-662.
• [28]Hoffmann A, Vieths S, Haustein D: Biologic allergen assay for in vivo test allergens with an in vitro model of the murine type I reaction. J Allergy Clin Immunol 1997, 99:227-232.
• [29]Ladics GS, van Bilsen JH, Brouwer HM, Vogel L, Vieths S, Knippels LM: Assessment of three human FcepsilonRI-transfected RBL cell-lines for identifying IgE induced degranulation utilizing peanut-allergic patient sera and peanut protein extract. Regul Toxicol Pharm 2008, 51:288-294.
• [30]Blanc F, Adel-Patient K, Drumare MF, Paty E, Wal JM, Bernard H: Capacity of purified peanut allergens to induce degranulation in a functional in vitro assay: Ara h 2 and Ara h 6 are the most efficient elicitors. Clin Exp Allergy 2009, 39:1277-1285.
• [31]Position paper: Allergen standardization and skin tests. The European Academy of Allergology and Clinical Immunology Allergy 1993, 48:48-82.
• [32]Schenk MF, Gilissen LJ, Esselink GD, Smulders MJ: Seven different genes encode a diverse mixture of isoforms of Bet v 1, the major birch pollen allergen. BMC Genomics 2006, 7:168. BioMed Central Full Text
• [33]Spangfort MD, Gajhede M, Osmark P, Poulsen FM, Ipsen H, Larsen JN, van Neerven RJ, Schou C, Lowenstein H: Three-dimensional structure and epitopes of Bet v 1. Int Arch Allergy Immunol 1997, 113:243-245.
• [34]Baker PJ, Britton KL, Rice DW, Rob A, Stillman TJ: Structural consequences of sequence patterns in the fingerprint region of the nucleotide binding fold. Implications for nucleotide specificity. J Mol Biol 1992, 228:662-671.
• [35]Friedl-Hajek R, Spangfort MD, Schou C, Breiteneder H, Yssel H, Joost van Neerven RJ: Identification of a highly promiscuous and an HLA allele-specific T-cell epitope in the birch major allergen Bet v 1: HLA restriction, epitope mapping and TCR sequence comparisons. Clin Exp Allergy 1999, 29:478-487.
• [36]Bousquet J, Hejjaoui A, Soussana M, Michel FB: Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. IV. Comparison of the safety and efficacy of two dosages of a high-molecular-weight allergoid. J Allergy Clin Immunol 1990, 85:490-497.
• [37]Bousquet J, Maasch HJ, Hejjaoui A, Skassa-Brociek W, Wahl R, Dhivert H, Michel FB: Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. III. Efficacy and safety of unfractionated and high-molecular-weight preparations in rhinoconjunctivitis and asthma. J Allergy Clin Immunol 1989, 84:546-556.
• [38]Lee TM, Grammer LC, Shaughnessy MA, Patterson R: Modified antigens in the treatment of allergic disease. Year Immunol 1986, 2:338-350.
• [39]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.
• [40]Tarzi M, Klunker S, Texier C, Verhoef A, Stapel SO, Akdis CA, Maillere B, Kay AB, Larche M: Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy. Clin Exp Allergy 2006, 36:465-474.
• [41]Purohit A, Niederberger V, Kronqvist M, Horak F, Gronneberg R, Suck R, Weber B, Fiebig H, van Hage M, Pauli G, et al.: Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives. Clin Exp Allergy 2008, 38(9):1514-1525.
• [42]van der Veen MJ, Mulder M, Witteman AM, van Ree R, Aalberse RC, Jansen HM, van der Zee JS: False-positive skin prick test responses to commercially available dog dander extracts caused by contamination with house dust mite (Dermatophagoides pteronyssinus) allergens. J Allergy Clin Immunol 1996, 98:1028-1034.
• [43]Trivedi B, Valerio C, Slater JE: Endotoxin content of standardized allergen vaccines. J Allergy Clin Immunol 2003, 111:777-783.
• [44]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.
• [45]Kahlert H, Suck R, Weber B, Nandy A, Wald M, Keller W, Cromwell O, Fiebig H: Characterization of a hypoallergenic recombinant Bet v 1 variant as a candidate for allergen-specific immunotherapy. Int Arch Allergy Immunol 2008, 145:193-206.
• [46]Niederberger V, Valenta R: Molecular approaches for new vaccines against allergy. Expert Rev Vaccines 2006, 5:103-110.
• [47]Vrtala S, Fohr M, Campana R, Baumgartner C, Valent P, Valenta R: Genetic engineering of trimers of hypoallergenic fragments of the major birch pollen allergen, Bet v 1, for allergy vaccination. Vaccine 2011, 29:2140-2148.
• [48]Jonsson F, Mancardi DA, Kita Y, Karasuyama H, Iannascoli B, Van Rooijen N, Shimizu T, Daeron M, Bruhns P: Mouse and human neutrophils induce anaphylaxis. J Clin Invest 2011, 121:1484-1496.
• [49]Aalberse RC, Stapel SO, Schuurman J, Rispens T: Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009, 39:469-477.
• [50]Potts JT Jr, Young DM, Anfinsen CB: Reconstitution of fully active RNase S by carboxypeptidase-degraded RNase S-peptide. J Biol Chem 1963, 238:2593-2594.
• [51]Corradin G, Harbury HA: Reconstitution of horse heart cytochrome c: interaction of the components obtained upon cleavage of the peptide bond following methionine residue 65. Proc Nat Acad Sci U S A 1971, 68:3036-3039.