Abstract

Mini Review

The use of Allergoids and Adjuvants in Allergen Immunotherapy

Celso Eduardo Olivier*

Published: 20 September, 2017 | Volume 1 - Issue 1 | Pages: 040-060

Allergen immunotherapy (AIT) is the unique curative treatment to help allergic patients to get over their allergies. With a personalized approach, AIT is the best example of precision medicine. After a century of intensive studies and innovative discoveries, allergists have in their hands many tools to orchestrate the best strategy to re-educate the hypersensitive immune systems that decrease the quality of life of their patients. This review describes both the historical and the promising acquisitions in this field, focusing the biochemical and Bioengineering tools that render an allergen more suitable for a secure, convenient and effective immunotherapy.

Read Full Article HTML DOI: 10.29328/journal.haard.1001006 Cite this Article Read Full Article PDF

Keywords:

Allergens; Allergoid; Allergists; Bioengineering; Hypersensitivity; Immunologic desensitization; Immune system; Polymerization; Precision medicine

References

  1. Akdis CA, Akdis Mb. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2011; 127: 18-27. Ref.: https://goo.gl/tfh5HN
  2. Curtis H. The immunization treatment of hay fever. JAMA. 1902; 39: 1267-1268. Ref.: https://goo.gl/djxtrJ
  3. Besredka A. De l'anaphylaxie. Sixiéme memoire de l'anaphylaxie lactique. Ann Inst Pasteur. 1909; 23: 166-174.
  4. Cobbold SP, Li XC. Translating Tolerogenic Therapies to the Clinic. Where Do We Stand and What are the Barriers? Front Immunol. 2012; 3: 317. Ref.: https://goo.gl/5sV5St
  5. Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005; 206: 232-259. Ref.: https://goo.gl/R7ZrtR
  6. Verheggen BG, Westerhout KY, Schreder CH, Augustin M. Health economic comparison of SLIT allergen and SCIT allergoid immunotherapy in patients with seasonal grass-allergic rhinoconjunctivitis in Germany. Clin Transl Allergy. 2015; 5: 1. Ref.: https://goo.gl/ySkzNy
  7. 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. Ref.: https://goo.gl/7P6pG1
  8. Olivier CE, Lima RPS, Argentão DGP, Silva MDd, Santos RAPG, et al. Group-specific Multi-allergen Sublingual/Swallow Immunotherapy Improves the Quality of Life of Polysensitized Children and Adults with Allergic Rhinitis. Journal of Allergy & Therapy. 2013; 4: 148. Ref.: https://goo.gl/3YGw5T
  9. Klimek L, Bachmann MF, Senti G, Kündig TM. Immunotherapy of type-1 allergies with virus-like particles and CpG-motifsExpert Rev Clin Immunol. 2014; 10: 1059-1067. Ref.: https://goo.gl/8BU7dK
  10. Cox L, Nelson H, Lockey R, Calabria C, Chacko T, et al. Allergen immunotherapy: A practice parameter third update. J Allergy Clin Immunol. 2011; 127: 1-55. Ref.: https://goo.gl/DMZKZX
  11. Palomares O, Martin-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, et al. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-beta. Genes Immun. 2014; 15: 511-520. Ref.: https://goo.gl/rRUDoJ
  12. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-Schmid B, et al. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol. 2007; 120: 707-713. Ref.: https://goo.gl/9d5zKm
  13. van Neerven RJ, Knol EF, Ejrnaes A, Würtzen PA. IgE-Mediated Allergen Presentation and Blocking Antibodies: Regulation of T-Cell Activation in Allergy. Int Arch Allergy Immunol. 2006; 141: 119-129. Ref.: https://goo.gl/WEn3nJ
  14. van de Veen W, Akdis M. Role of IgG4 in IgE-mediated allergic responses. J Allergy Clin Immunol. 2016; 138: 1434-1435. Ref.: https://goo.gl/xBamCk
  15. van de Veen W, Stanic B, Wirz OF, Jansen K, Globinska A, et al. Role of regulatory B cells in immune tolerance to allergens and beyond. J Allergy Clin Immunol. 2016; 138: 654-665. Ref.: https://goo.gl/RkAGsz
  16. Noval Rivas M, Chatila TA. Regulatory T cells in allergic diseases. J Allergy Clin Immunol. 2016; 138: 639-652. Ref.: https://goo.gl/KTJB9v
  17. Till SJ, Francis JN, Nouri-Aria K, Durham SR. Mechanisms of immunotherapy. J Allergy Clin Immunol. 2004; 113: 1025-1034. Ref.: https://goo.gl/aG2qBv
  18. Favre L, Spertini F, Corthesy B. Secretory IgA Possesses Intrinsic Modulatory Properties Stimulating Mucosal and Systemic Immune Responses. J Immunol. 2005; 175: 2793-2800. Ref.: https://goo.gl/Tvr6jn
  19. Aalberse RC, Schuurman J. IgG4 breaking the rules. Immunology. 2002; 105: 9-19. Ref.: https://goo.gl/XCMzQS
  20. Focke M, Swoboda I, Marth K, Valenta R. Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity. Clin Exp Allergy. 2010; 40: 385-397. Ref.: https://goo.gl/pxwjA8
  21. Himly M, Carnes J, Fernandez-Caldas E, Briza P, Ferreira F. Characterization of allergoids. Arb Paul Ehrlich Inst Bundesinstitut Impfstoffe Biomed Arzneim Langen Hess. 2009; 96: 61-69. Ref.: https://goo.gl/Kmp9mY
  22. Maasch H, Marsh D. Standardized extracts modified allergens-allergoids. Clin Rev Allergy. 1987; 5: 89-106. Ref.: https://goo.gl/2DJnDL
  23. Loewenstein E. Über aktive Schutzimpfung bei Tetanus durch Toxoide. Zeitschrift für Hygiene und Infektionskrankheiten. 1909; 62: 491-508. Ref.: https://goo.gl/XQMVkW
  24. Bousquet J, Maasch HJ, Hejjaoui A, Skassa-Brociek W, Wahl Rd, et al. 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. Ref.: https://goo.gl/ZZ83hP
  25. Valenta R, Ferreira F, Focke-Tejkl M, Linhart B, Niederberger V, et al. From Allergen Genes to Allergy Vaccines. Annu Rev Immunol. 2010; 28: 211-241. Ref.: https://goo.gl/is9XQy
  26. Heath M, Bell A, Skinner M, Bullimore AD. Molecular Fingerprinting of Complex Allergoids. Journal of Allergy and Clinical Immunology. 2016; 137: 405. Ref.: https://goo.gl/3hn6tp
  27. Starchenka S, Bell AJ, Mwange J, Skinner MA, Heath MD. Molecular fingerprinting of complex grass allergoids: size assessments reveal new insights in epitope repertoires and functional capacities. World Allergy Organ J. 2017; 10: 17. Ref.: https://goo.gl/z1eanS
  28. Heath M, Starchenka S, Bell A, Skinner M. Structural and immunological characterisation of a broad-spectrum grass allergoid vaccine. Journal of Allergy and Clinical Immunology. 2017; 139: 259. Ref.: https://goo.gl/9cLRVL
  29. 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. Ref.: https://goo.gl/Ni95rP
  30. Distler A, Pappelendam D. 13-year overview of serious adverse drug reactions following subcutaneous specific immunotherapy with a chemically modified allergen preparation. Allergo J Int. 2015; 24: 294-302. Ref.: https://goo.gl/XMYanV
  31. Pickl WF. The Value of Identifying Major T Cell Epitopes of Clinically Important Allergens. Int Arch Allergy Immunol. 2012; 160: 4-6. Ref.: https://goo.gl/UU2kBk
  32. Campbell JD, Buckland KF, McMillan SJ, Kearley J, Oldfield WLG, et al. Peptide immunotherapy in allergic asthma generates IL-10“dependent immunological tolerance associated with linked epitope suppression. J Exp Med. 2009; 206: 1535-1547. Ref.: https://goo.gl/ksBJbT
  33. Campana R, Moritz K, Marth K, Neubauer A, Huber H, et al. Frequent occurrence of T cell-mediated late reactions revealed by atopy patch testing with hypoallergenic rBet v 1 fragments. J Allergy Clin Immunol. 2016; 137: 601-609. Ref.: https://goo.gl/SHUYhp
  34. Ferreira F, Wolf M, Wallner M. Molecular Approach to Allergy Diagnosis and Therapy. Yonsei Med J. 2014; 55: 839-852. Ref.: https://goo.gl/oT5eqW
  35. Flower DR. Advances in Predicting and Manipulating the Immunogenicity of Biotherapeutics and Vaccines. BioDrugs. 2009; 23: 231-240. Ref.: https://goo.gl/hkWfmH
  36. Olivier CE, Argentão DGP, Santos RAPG, Silva MD, Lima RPS, et al. Skin scrape test: an inexpensive and painless skin test for recognition of immediate hypersensitivity in children and adults. The Open Allergy Journal. 2013; 6: 9-17. Ref.: https://goo.gl/XHJx2z
  37. Olivier CE, Argentão DG, Santos Lima RP, Santos RAGP, Fabbri N. Assessment of allergen-induced respiratory hyperresponsiveness before the prescription of a specific immunotherapy. Allergy Rhinol (Providence). 2015; 6: 89-93. Ref.: https://goo.gl/tJcbVM
  38. Gioacchino MD, Cavallucci E, Ballone E, Cervone M, Rocco PD, et al. Dose-Dependent Clinical and Immunological Efficacy of Sublingual Immunotherapy with Mite Monomeric Allergoid. Int J Immunopathol Pharmacol. 2012; 25: 671-679. Ref.: https://goo.gl/xrDSio
  39. Iraola V, Gallego MT, Lopez-Matas MA, Morales M, Bel I, et al. Immunogenicity of Phleum pratense depigmented allergoid vaccines: experimental study in rabbits. J Investig Allergol Clin Immunol. 2012; 22: 35-40. Ref.: https://goo.gl/crE4xR
  40. Olivier CE, Lima RPS, Pinto DG, Santos RAPG, Silva GKM, et al. In search of a tolerance-induction strategy for cow's milk allergies: significant reduction of beta-lactoglobulin allergenicity via transglutaminase/cysteine polymerization. Clinics (Sao Paulo). 2012; 67: 1171-1179. Ref.: https://goo.gl/AS4Ntz
  41. Egger M, Jürets A, Wallner M, Briza P, Ruzek S, et al. Assessing Protein Immunogenicity with a Dendritic Cell Line-Derived Endolysosomal Degradome. PLoS One. 2011; 6: 17278. Ref.: https://goo.gl/5Ytj7Y
  42. Thomson DMP. Assessment of immune status by the leukocyte adherence inhibition test. New York: Academic Press; 1982. Ref.: https://goo.gl/CoMKWN
  43. Vanto T, Smogorzewska EM, Viander M, Kalimo K, Koivikko A. Leukocyte migration inhibition test in children with cow milk allergy. Allergy 1987; 42: 612-618. Ref.: https://goo.gl/gHfAHJ
  44. Moingeon P. Adjuvants for allergy vaccines. Hum Vaccin Immunother. 2012; 8: 1492-1498. Ref.: https://goo.gl/UbMQjZ
  45. Häfner D, Gödicke V, Narkus A. Allergen specific immunotherapy has no influence on standard chemistry and hematology laboratory parameters in clinical studies. Clin Transl Allergy. 2014; 4: 18. Ref.: https://goo.gl/qsWcvj
  46. Buczyłko K, van der Werf JF, Boot D, van Ree R. Accelerated Up-Dosing of Subcutaneous Immunotherapy with a Registered Allergoid Birch Pollen Preparation. Int Arch Allergy Immunol. 2017; 172: 183-186. Ref.: https://goo.gl/ACPT69
  47. Pfaar O, Lang S, Pieper-Fürst U, Astvatsatourov A, Gerich F, et al. Ultra-short-course booster is effective in recurrent grass pollen-induced allergic rhinoconjunctivitis. Allergy. 2017; 4: 13240. Ref.: https://goo.gl/tHDXJu
  48. Chaker AM, Al-Kadah B, Luther U, Neumann U, Wagenmann M. An accelerated dose escalation with a grass pollen allergoid is safe and well-tolerated: a randomized open label phase II trial. Clin Transl Allergy. 2016; 6: 4. Ref.: https://goo.gl/Be7XLh
  49. Morais-Almeida M, Arêde C, Sampaio G, Borrego LM. Ultrarush schedule of subcutaneous immunotherapy with modified allergen extracts is safe in paediatric age. Asia Pac Allergy. 2016; 6: 35-42. Ref.: https://goo.gl/PeD17K
  50. Noon L. Prophylatic inoculation against hay fever. The Lancet 1911; 177:1572-1573. Ref.: https://goo.gl/v9EHqm
  51. Cooke RA, Veer AV. Human Sensitization. The Journal of Immunology. 1916; 1: 201-305. Ref.: https://goo.gl/XBU9FK
  52. Schloss OM. A Case of Allergy to Common Foods. Am J Dis Child 1983; 41:249-252. Ref.: https://goo.gl/VHAoEQ
  53. Coca AF. Studies in Specific Hypersensitiveness V. The Preparation of Fluid Extracts and Solutions for Use in the Diagnosis and Treatment of the Allergies with Notes on the Collection of Pollens. The Journal of Immunology. 1922; 7: 163-178. Ref.: https://goo.gl/VmhWy6
  54. Van Metre Jr TE, Rosenberg GL, Vaswani SK, Ziegler SR, Adkinson NF. Pain and dermal reaction caused by injected glycerin in immunotherapy solutions. J Allergy Clin Immunol. 1996; 97: 1033-1039. Ref.: https://goo.gl/fvcFoV
  55. Daigle BJ, Rekkerth DJ. Practical recommendations for mixing allergy immunotherapy extracts. Allergy Rhinol (Providence). 2015; 6: 1-7. Ref.: https://goo.gl/GQ266R
  56. Slater JE, Menzies SL, Bridgewater J, Mosquera A, Zinderman CE, et al. The US Food and Drug Administration review of the safety and effectiveness of nonstandardized allergen extracts. J Allergy Clin Immunol. 2012; 129: 1014-1019. Ref.: https://goo.gl/jT6dv2
  57. Fernández-Caldas E, Gallego M, Carnés J, Iraola V. Enzymatic Activity of Dermatophagoides pteronyssinus extracts after acidic treatment. Int Arch Allergy Immunol. 2008; 145: 298-304. Ref.: https://goo.gl/azdfme
  58. Iraola VM, Leonor JR, Morales M, López Matas MA, Gallego MT, Carnés J. Enzymatic Activity of Grass Native Allergenic Extracts Is Eliminated in Depigmented Allergoids. Journal of Allergy and Clinical Immunology. 2013; 131: 110. Ref.: https://goo.gl/Eei5fQ
  59. Pfaar O, Sager A, Robinson DS. Safety and effect on reported symptoms of depigmented polymerized allergen immunotherapy: a retrospective study of 2927 paediatric patients. Pediatr Allergy Immunol. 2015; 26: 280-286. Ref.: https://goo.gl/EGN6rz
  60. Johansen P, Senti G, Gómez JMM, Wüthrich B, Bot A, et al. Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens. Eur J Immunol. 2005; 35: 3591-3598. Ref.: https://goo.gl/9ryW7X
  61. Davis PJ, Williams SC. Protein modification by thermal processing. Allergy. 1998; 53: 102-105. Ref.: https://goo.gl/nxXkWm
  62. Hildebrandt S, Kratzin HD, Schaller R, Fritsché R, Steinhart H, et al. In Vitro Determination of the Allergenic Potential of Technologically Altered Hen's Egg. J Agric Food Chem. 2008; 56: 1727-1733. Ref.: https://goo.gl/Jhm5Bs
  63. Kim JS, Nowak-Wegrzyn A, Sicherer SH, Noone S, Moshier EL, et al. Dietary baked milk accelerates the resolution of cow's milk allergy in children. J Allergy Clin Immunol. 2011; 128: 125-131. Ref.: https://goo.gl/LtRSCy
  64. Beyer K, Morrow E, Li XM, Bardina L, Bannon GA, et al. Effects of cooking methods on peanut allergenicity. J Allergy Clin Immunol. 2001; 107: 1077-1081. Ref.: https://goo.gl/oXEDkY
  65. Naterman HL. Formalinized pollen tannate in desensitization treatment. J Allergy. 1957; 28: 76-83. Ref.: https://goo.gl/YTt7cF
  66. Ishizaka K, Okudaira H, King TP. Immunogenic Properties of Modified Antigen E - Ability of Urea-Denatured Antigen and alpha-Polypeptide Chain to Prime T Cells Specific for Antigen E. J Immunol. 1975; 114: 110-115. Ref.: https://goo.gl/yFPnWF
  67. 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. Ref.: https://goo.gl/V65UeX
  68. Avrameas S. Coupling of enzymes to proteins with glutaraldehyde. Immunochemistry. 1969; 6: 43-52.
  69. Avrameas S, Ternynck T. The Cross-linking of Proteins with Glutaraldehyde and its use for the preparation of immunoadsorbents. Immunochemistry. 1969; 6: 53-66. Ref.: https://goo.gl/65CFhq
  70. Haddad ZH, Marsh DG, Campbell DH. Studies on "allergoids" prepared from naturally occurring allergens II. Evaluation of allergenicity and assay of antigenicity of formalinized mixed grass pollen extracts. J Allergy Clin Immunol. 1972; 49: 197-209. Ref.: https://goo.gl/jn2uPK
  71. Urry ZL, Richards DF, Black C, Morales M, Carnes J, et al. Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1-alpha, 25-dihydroxyvitamin D3. BMC Immunol. 2014; 15: 21. Ref.: https://goo.gl/PzdNDC
  72. Casanovas M, Gómez MJ, Carnés J, Fernández-Caldas E. Skin tests with native, depigmented and glutaraldehyde polymerized allergen extracts. J Invest Allergol Clin Immunol. 2005; 15: 30-36. Ref.: https://goo.gl/uU5k4H
  73. Norman PS, Lichtenstein LM, Marsh DG. Studies on allergoids from naturally occurring allergens. IV. Efficacy and safety of long-term allergoid treatment of ragweed hay fever. J Allergy Clin Immunol. 1981; 68: 460-470. Ref.: https://goo.gl/fs4jrx
  74. Kalinski P, Lebre MC, Kramer D, De Jong EC, Van Schijndel JW, et al. Analysis of the CD4+ T cell responses to house dust mite allergoid. Allergy. 2003; 58: 648-656. Ref.: https://goo.gl/yAjJuU
  75. Salgado J, Casadevall G, Puigneró V, Queralt J. Characterization of Allergoids from Ovalbumin in vitro and in vivo. Immunobiology. 1996; 196: 375-386. Ref.: https://goo.gl/nBiK4B
  76. Patterson R, Suszko IM, McIntire FC. Polymerized Ragweed Antigen E I. Preparation and Immunologic Studies. J Immunol. 1973; 110: 1402-1412. Ref.: https://goo.gl/us2gBc
  77. Patterson R, Suszko IM, Pruzansky JJ, Zeiss CR. Polymerized Ragweed Antigen E II. In vivo Elimination Studies and Reactivity with IgE Antibody Systems. J Immunol. 1973; 110: 1413-1418. Ref.: https://goo.gl/Kioi5r
  78. Patterson R, Suszko IM, Pruzansky JJ, Zeiss CR, Metzger WJ, et al. Polymerization of mixtures of grass allergens. J Allergy Clin Immunol. 1977; 59: 314-319. Ref.: https://goo.gl/LNeHnw
  79. Gallego MT, Iraola V, Himly M, Robinson DS, Badiola C, et al. Depigmented and polymerised house dust mite allergoid: allergen content, induction of IgG4 and clinical response. Int Arch Allergy Immunol. 2010; 153: 61-69. Ref.: https://goo.gl/N1GRGR
  80. HayGlass KT, Strejan GH. Antigen- and IgE class-specific suppression mediated by T suppressor cells of mice treated with glutaraldehyde-polymerized ovalbumin. Int Arch Allergy Appl Immunol. 1983; 71: 23-31. Ref.: https://goo.gl/eSGzdA
  81. Morales M, Gallego M, Iraola V, Taulés M, de Oliveira E, et al. In vitro evidence of efficacy and safety of a polymerized cat dander extract for allergen immunotherapy. BMC Immunol. 2017; 18: 10. Ref.: https://goo.gl/ovxFDV
  82. Heydenreich B, Bellinghausen I, Lorenz S, Henmar H, Strand D, et al. Reduced in vitro T-cell responses induced by glutaraldehyde-modified allergen extracts are caused mainly by retarded internalization of dendritic cells. Immunology. 2012; 136: 208-217. Ref.: https://goo.gl/aNcFTJ
  83. Villas-Boas MB, Vieira KP, Trevizan G, Zollner RL, Netto FM. The effect of transglutaminase-induced polymerization in the presence of cysteine on beta-lactoglobulin antigenicity. Int Dairy J. 2010; 20: 386-392. Ref.: https://goo.gl/RdN37z
  84. Hendrix S, Zeiss CR, Suszko I, Levitz D, Patterson R. Polymerized whole ragweed: An improved method of immunotherapy. J Allergy Clin Immunol. 1978; 62: 289-294. Ref.: https://goo.gl/vvK5Ys
  85. Mistrello G, Roncarolo D, Gentili M, Zanoni D, Falagiani P. Modified par j I allergen from P. judaica pollen and its rate of absorption in rats. Immunol Lett. 1994; 40: 31-36. Ref.: https://goo.gl/BrLzif
  86. Akdis CA, Barlan IB, Bahceciler N, Akdis M. Immunological mechanisms of sublingual immunotherapy. Allergy. 2006; 61: 11-14. Ref.: https://goo.gl/qixFuZ
  87. Manzano AI, Javier Cañada F, Cases B, Sirvent S, Soria I, et al. Structural studies of novel glycoconjugates from polymerized allergens (allergoids) and mannans as allergy vaccines. Glycoconj J. 2016; 33: 93-101. Ref.: https://goo.gl/5wwQQR
  88. Roger A, Depreux N, Jurgens Y, Heath MD, Garcia G, et al. A novel and well tolerated mite allergoid subcutaneous immunotherapy: evidence of clinical and immunologic efficacy. Immun Inflamm Dis. 2014; 2: 92-98. Ref.: https://goo.gl/kG9DuY
  89. Gokmen NM, Ersoy R, Gulbahar O, Ardeniz O, Sin A, et al. Desensitization effect of preseasonal seven-injection allergoid immunotherapy with olive pollen on basophil activation: the efficacy of olive pollen-specific preseasonal allergoid immunotherapy on basophils. Int Arch Allergy Immunol. 2012; 159: 75-82. Ref.: https://goo.gl/GvwL8J
  90. Pfaar O, Sager A, Robinson DS. Safety and effect on reported symptoms of depigmented-polymerised allergen immunotherapy: a retrospective study of 2927 paediatric patients. Pediatr Allergy Immunol. 2015. 26: 280-286. Ref.: https://goo.gl/cUsWgY
  91. Lozano J, Cruz MJ, Piquer M, Giner MT, Plaza AM. Assessing the Efficacy of Immunotherapy with a Glutaraldehyde-Modified House Dust Mite Extract in Children by Monitoring Changes in Clinical Parameters and Inflammatory Markers in Exhaled Breath. Int Arch Allergy Immunol. 2014; 165: 140-147. Ref.: https://goo.gl/QsZAFC
  92. Weinberger EE, Himly M, Myschik J, Hauser M, Altmann F, et al. Generation of hypoallergenic neoglycoconjugates for dendritic cell targeted vaccination: a novel tool for specific immunotherapy. J Control Release. 2013; 165: 101-109. Ref.: https://goo.gl/mL2YMf
  93. Aboumahmoud R, Savello P. Crosslinking of Whey Protein by Transglutaminase. J Dairy Sci. 1990; 73: 256-263. Ref.: https://goo.gl/tv8YTK
  94. Jaros D, Partschefeld C, Henle T, Rohm H. Transglutaminase in dairy products: chemistry, physics, applications. J Texture Studies. 2006; 37: 113-155. Ref.: https://goo.gl/2pWLyW
  95. Cozzolino A, Di Pierro P, Mariniello L, Sorrentino A, Masi P, et al. Incorporation of whey proteins into cheese curd by using transglutaminase. Biotechnol Appl Biochem. 2003; 38: 289-295. Ref.: https://goo.gl/8inU3j
  96. Eissa AS, Puhl C, Kadla JF, Khan SA. Enzymatic Cross-Linking of β-Lactoglobulin: conformational properties using FTIR Spectroscopy. Biomacromolecules. 2006; 7: 1707-1713. Ref.: https://goo.gl/6aovxp
  97. Greenberg CS, Birckbichler PJ, Rice RH. Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J. 1991; 5: 3071-3077. Ref.: https://goo.gl/wGyHFm
  98. Pedersen MH, Hansen TK, Sten E, Seguro K, Ohtsuka T, et al. Evaluation of the potential allergenicity of the enzyme microbial transglutaminase using the 2001 FAO/WHO Decision Tree. Mol Nutr Food Res. 2004; 48: 434-440. Ref.: https://goo.gl/2v1ghj
  99. Olivier CE, Villas-Boas MB, Netto FM, Zollner RL. Allergenicity of Bos d 5 in Children with Cow’s Milk Allergy is Reduced by Transglutaminase Polymerization. Ped Allergy Immunol Pulmonol. 2012; 25: 30-33. Ref.: https://goo.gl/7BUHna
  100. Giosafatto CVL, Rigby NM, Wellner N, Ridout M, Husband F, et al. Microbial transglutaminase-mediated modification of ovalbumin. Food Hydrocolloids. 2012; 26: 261-267. Ref.: https://goo.gl/rN9PMM
  101. Villas-Boas MB, Fernandes MA, Zollner RdL, Netto FM. Effect of polymerization with transglutaminase on in vitro digestion and antigenicity of beta-lactoglobulin. Int Dairy J. 2012; 25: 123-131. Ref.: https://goo.gl/G3vyy9
  102. Damodaran S, Li Y. A two-step enzymatic modification method to reduce immuno-reactivity of milk proteins. Food Chem. 2017; 237: 724-732. Ref.: https://goo.gl/rY5ZmP
  103. Mistrello G, Brenna O, Roncarolo D, Zanoni D, Gentili M, et al. Monomeric chemically modified allergens: Immunologic and physicochemical characterization. Allergy. 1996; 51: 8-15. Ref.: https://goo.gl/WRFJAf
  104. Nguyen NT, Raskopf E, Shah-Hosseini K, Zadoyan G, Mösges R. A review of allergoid immunotherapy: is cat allergy a suitable target? Immunotherapy. 2016; 8: 331-349. Ref.: https://goo.gl/CvSvQ2
  105. Lombardi C, Gargioni S, Melchiorre A, Tiri A, Falagiani P, et al. Safety of sublingual immunotherapy with monomeric allergoid in adults: multicenter post-marketing surveillance study. Allergy. 2001; 56: 989-992. Ref.: https://goo.gl/TL2Egx
  106. Hüser C, Dieterich P, Singh J, Shah-Hosseini K, Allekotte S, et al. A 12-week DBPC dose-finding study with sublingual monomeric allergoid tablets in house dust mite-allergic patients. Allergy. 2016; 72: 77-84. Ref.: https://goo.gl/F8svNS
  107. Scalone G, Compalati E, Bruno ME, Mistrello G. Effect of two doses of carbamylated allergoid extract of dust mite on nasal reactivity. Eur Ann Allergy Clin Immunol. 2013; 45: 193-200. Ref.: https://goo.gl/f3dJcX
  108. Mösges R, Ritter B, Kayoko G, Passali D, Allekotte S. Carbamylated monomeric allergoids as a therapeutic option for sublingual immunotherapy of dust mite- and grass pollen-induced allergic rhinoconjunctivitis: a systematic review of published trials with a meta-analysis of treatment using Lais® tablets. Acta Dermatovenerologica APA. 2010; 19: 3-10. Ref.: https://goo.gl/vfJ3Nr
  109. Hüser C, Dieterich P, Singh J, Shah-Hosseini K, Allekotte S, et al. A 12‐week DBPC dose‐finding study with sublingual monomeric allergoid tablets in house dust mite‐allergic patients. Allergy. 2017; 72: 77-84. Ref.: https://goo.gl/rFyDj8
  110. Agostinis F, Tellarini L, Canonica GW, Falagiani P, Passalacqua G. Safety of sublingual immunotherapy with a monomeric allergoid in very young children. Allergy 2005; 60:133. Ref.: https://goo.gl/za4oTu
  111. D'Anneo RW, Arena A, Gammeri E, Bruno ME, Falagiani P, et al. Parietaria sublingual allergoid immunotherapy with a co-seasonal treatment schedule. Allergologia et Immunopathologia. 2008; 45: 79-84. Ref.: https://goo.gl/wWRmKK
  112. Shershakova N, Bashkatova E, Babakhin A, Andreev S, Nikonova A, et al. Allergen-Specific Immunotherapy with Monomeric Allergoid in a Mouse Model of Atopic Dermatitis. PLoS ONE. 2015; 10. Ref.: https://goo.gl/4jHorH
  113. Zivny JH, Moldoveanu Z, Vu HL, Russell MW, Mestecky J, et al. Mechanisms of Immune Tolerance to Food Antigens in Humans. Clin Immunol. 2001; 101: 158-68. Ref.: https://goo.gl/kEtK3Z
  114. Larché M. Immunotherapy with Allergen Peptides. Allergy, Asthma, and Clinical . 2007; 3: 53-59. Ref.: https://goo.gl/Fm56Pw
  115. Geysen HM, Rodda SJ, Mason TJ. A priori delineation of a peptide which mimics a discontinuous antigenic determinant. Mol Immunol. 1986; 23:7 09-715. Ref.: https://goo.gl/jQ4C6E
  116. Sibilano R, Frossi B, Pucillo CE. Mast cell activation: A complex interplay of positive and negative signaling pathways. Eur J Immunol. 2014; 44: 2558-2566. Ref.: https://goo.gl/hwVx3J
  117. Lambrakis P, Rushworth GF, Adamson J, Leslie SJ. Aspirin hypersensitivity and desensitization protocols: implications for cardiac patients Ther Adv Drug Saf. 2011; 2: 263-270. Ref.: https://goo.gl/LvKewX
  118. Morris DL. Intradermal testing and sublingual desensitization for nickel. Cutis 1998; 61: 129-132. Ref.: https://goo.gl/DQGo1H
  119. Majewska-Szczepanik M, Strzepa A, Drozynska I, Motyl S, Banach T, et al. Epicutaneous immunization with hapten-conjugated protein antigen alleviates contact sensitivity mediated by three different types of effector cells. Pharmacological Reports 2012; 64: 919-926. Ref.: https://goo.gl/XRUjXN
  120. Gadermaier E, James LK, Shamji MH, Blatt K, Fauland K, et al. Epitope specificity determines cross-protection of a SIT-induced IgG(4) antibody. Allergy. 2016; 71: 36-46. Ref.: https://goo.gl/ZCuqWf
  121. Luzar J, Štrukelj B, Lunder M. Phage display peptide libraries in molecular allergology: from epitope mapping to mimotope-based immunotherapy. Allergy. 2016; 71: 1526-1532. Ref.: https://goo.gl/hWW7N1
  122. Olivier CE. Food Allergy. J Aller Ther. 2013; S3: 1-7. Ref.: https://goo.gl/ztUVpk
  123. Untersmayr E, Scholl I, Swoboda I, Beil WJ, Forster-Waldl E, et al. Antacid medication inhibits digestion of dietary proteins and causes food allergy: a fish allergy model in BALB/c mice. J Allergy Clin Immunol. 2003; 112: 616-623. Ref.: https://goo.gl/2gZ5Tt
  124. Pecquet S, Bovetto L, Maynard F, Fritsché R. Peptides obtained by tryptic hydrolysis of bovine Beta-lactoglobulin induce specific oral tolerance in mice J Allergy Clin Immunol. 2000; 105: 514-521. Ref.: https://goo.gl/dVhfQg
  125. Astwood JD, Leach JN, Fuchs RL. Stability of food allergens to digestion in vitro. Nat Biotechnol. 1996; 14: 1269-1273. Ref.: https://goo.gl/GQP8Es
  126. Lucas JS, Cochrane SA, Warner JO, Hourihane JO. The effect of digestion and pH on the allergenicity of kiwifruit proteins. Pediatr Allergy Immunol. 2008; 19: 392-398. Ref.: https://goo.gl/dFfop6
  127. Untersmayr E, Poulsen LK, Platzer MH, Pedersen MH, Boltz-Nitulescu, et al. The effects of gastric digestion on codfish allergenicity. J Allergy Clin Immunol. 2005; 115: 377-382. Ref.: https://goo.gl/NG5TLA
  128. Olivier CE, Lima RPdS, Argentão DGP, Silva MDd, Santos RAPGd, et al. The immunodominant allergen of genetically improved farmed tilapia (Oreochromis niloticus)is a 100-kDa protein susceptible to pepsin digestion in four fish-allergic Brazilian patients. Braz J Aller Immunol. 2015; 3: 261-265.
  129. Tavano OL. Protein hydrolysis using proteases: An important tool for food biotechnology. J Molecular Catalysis B: Enzymatic. 2013; 90: 1-11. Ref.: https://goo.gl/EvVYov
  130. Fritsché R. Induction of oral tolerance to cow's milk proteins in rats fed with a whey protein hydrolysate. Nutrition Research. 1998; 18: 1335-1341. Ref.: https://goo.gl/EBUExX
  131. Hacini-Rachinel F, Vissers YM, Doucet-Ladevéze R, Blanchard C, Demont A, et al. Low-Allergenic Hydrolyzed Egg Induces Oral Tolerance in Mice. Int Arch Aller Immunol. 2014; 164: 64-73. Ref.: https://goo.gl/9wLxku
  132. Esch BCAMv, Schouten B, Kivit Sd, Hofman GA, Knippels, et al. Oral tolerance induction by partially hydrolyzed whey protein in mice is associated with enhanced numbers of Foxp3+ regulatory T-cells in the mesenteric lymph nodes. Pediatr Allergy Immunol. 2011; 22: 820-826. Ref.: https://goo.gl/srhqbU
  133. Fritsché R, Pahud JJ, Pecquet S, Pfeifer A. Induction of systemic immunologic tolerance to beta-lactoglobulin by oral administration of a whey protein hydrolysate. J Aller Clinical Immunol. 1997; 100: 266-273. Ref.: https://goo.gl/c2fyT5
  134. Yang M, Yang C, Nau Fo, Pasco M, Juneja LR, et al. Immunomodulatory Effects of Egg White Enzymatic Hydrolysates Containing Immunodominant Epitopes in a BALB/c Mouse Model of Egg Allergy. J Agricul Food Chem. 2009; 57: 2241-2248. Ref.: https://goo.gl/mRDpFG
  135. Vaarala O, Saukkonen T, Savilahti E, Klemola T, Akerblom HK. Development of immune response to cow's milk proteins in infants receiving cow's milk or hydrolyzed formula. J Aller Clinical Immunol. 1995; 96: 917-923. Ref.: https://goo.gl/z37dcz
  136. Lanzavecchia A, Frühwirth A, Perez L, Corti D. Antibody-guided vaccine design: identification of protective epitopes. Curr Opin Immunol. 2016; 41: 62-67. Ref.: https://goo.gl/HFZHaL
  137. de Lalla C, Sturniolo T, Abbruzzese L, Hammer J, Sidoli A, et al. Identification of Novel T Cell Epitopes in Lol p5a by Computational Prediction. J Immunol. 1999; 163: 1725-1729. Ref.: https://goo.gl/1yX5Wf
  138. Nielsen M, Lundegaard C, Worning P, Hvid CS, Lamberth K, et al. Improved prediction of MHC class I and class II epitopes using a novel Gibbs sampling approach. Bioinformatics. 2004; 20: 1388-1397. Ref.: https://goo.gl/Nb2Wkr
  139. Dhiraj H, Paul RY, David PF. Current status of short synthetic peptides as vaccines. Med Chem. 2006; 2: 627-646. Ref.: https://goo.gl/jmXwPN
  140. Merrifield RB. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J American Chem Society. 1963; 85: 2149-2154. Ref.: https://goo.gl/AiZywi
  141. Geysen HM, Meloen RH, Barteling SJ. Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid. Proc Natl Acad Sci U S A. 1984; 81: 3998-4002. Ref.: https://goo.gl/tVhwS6
  142. Sumar N. Multiple pin peptide scanning ("Pepscan"). In: Westwood OMR, Hay FC, editors. Epitope mapping -A Pratical approach. 2001; 17-42.
  143. 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 Letters. 1997; 408: 285-288. Ref.: https://goo.gl/QEJADG
  144. Fellrath J-M, Kettner A, Dufour N, Frigerio C, Schneeberger D, et al. Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: Results of a phase I trial. J Aller Clinical Immunol. 2003; 111: 854-861. Ref.: https://goo.gl/bZMnZ3
  145. 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. Ref.: https://goo.gl/qL1TrV
  146. Norman PS, Jr JLO, Long AA, Creticos PS, Gefter MA, et al. Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med. 1996; 154: 1623-1628. Ref.: https://goo.gl/qZhkSs
  147. Müller U, Akdis CA, Fricker M, Akdis M, Blesken T, 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. Ref.: https://goo.gl/7wStu9
  148. Marcotte GV, Braun CM, Norman PS, Nicodemus CF, Kagey-Sobotka A, et al. Effects of peptide therapy on ex vivo T-cell responses. J Allergy Clinical Immunol. 1998; 101: 506-513. Ref.: https://goo.gl/mkckrx
  149. Oldfield WLG, Larché 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. Ref.: https://goo.gl/t7S4qT
  150. Pellaton C, Perrin Y, Boudousquié C, Barbier N, Wassenberg J, et al. Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides. Clinical and Translational Allergy. 2013; 3: 17. Ref.: https://goo.gl/9aaBXc
  151. Spertini F, Perrin Y, Audran R, Pellaton C, Boudousquié C, et al. Safety and immunogenicity of immunotherapy with Bet v 1 derived contiguous overlapping peptides. J Aller Clinical Immunol. 2014; 134: 239-240. Ref.: https://goo.gl/qPPi38
  152. Spertini F, DellaCorte G, Kettner A, de Blay F, Jacobsen L, et al. Efficacy of 2 months of allergen-specific immunotherapy with Bet v 1-derived contiguous overlapping peptides in patients with allergic rhinoconjunctivitis: Results of a phase IIb study. J Aller Clinical Immunol. 2016; 138: 162-168. Ref.: https://goo.gl/WidJ2w
  153. Stephen SL, Sivanandam VG, Kochanek S. Homologous and heterologous recombination between adenovirus vector DNA and chromosomal DNA. J Gene Medicine. 2008; 10: 1176-1189. Ref.: https://goo.gl/gaCZho
  154. Chen K-W, Blatt K, Thomas WR, Swoboda I, Valent P, et al. Hypoallergenic Der p 1/Der p 2 combination vaccines for immunotherapy of house dust mite allergy. J Allergy Clin Immunol. 2012; 130: 435-443. Ref.: https://goo.gl/5DfTFL
  155. Bouchaud G, Braza F, Chesnà J, Lair D, Chen K-W, et al. Prevention of allergic asthma through Der p 2 peptide vaccination. J Allergy Clin Immunol. 2015; 136: 197-200. Ref.: https://goo.gl/LcWHqr
  156. Ferreira F, Hirthenlehner K, Briza P, Breiteneder H, Scheiner O, et al. Isoforms of atopic allergens with reduced allergenicity but conserved T cell antigenicity: possible use for specific immunotherapy. Int Arch Allergy Immunol. 1997; 113: 125-127. Ref.: https://goo.gl/mFwSYP
  157. Zaborsky N, Brunner M, Wallner M, Himly M, Karl T, et al. Antigen Aggregation Decides the Fate of the Allergic Immune Response. J Immunol. 2010; 184: 725-735. Ref.: https://goo.gl/1rHNJ9
  158. Chen KW, Focke-Tejkl M, Blatt K, Kneidinger M, Gieras A, et al. Carrier-bound nonallergenic Der p 2 peptides induce IgG antibodies blocking allergen-induced basophil activation in allergic patients. Allergy. 2012; 67: 609-621. Ref.: https://goo.gl/zWFxLB
  159. Wiedermann U, Jahn-Schmid B, Lindblad M, Rask C, Holmgren J, et al. Suppressive versus stimulatory effects of allergen/cholera toxoid (CTB) conjugates depending on the nature of the allergen in a murine model of type I allergy. Int Immunol. 1999; 11: 1131-1138. Ref.: https://goo.gl/aVLbpH
  160. Cornelius C, Schöneweis K, Georgi F, Weber M, Niederberger V, et al. Immunotherapy With the PreS-based Grass Pollen Allergy Vaccine BM32 Induces Antibody Responses Protecting Against Hepatitis B Infection. EBioMedicine. 2016; 11: 58-67. Ref.: https://goo.gl/rLFeci
  161. Pichler U, Hauser M, Hofer H, Himly M, Hoflehner E, et al. Allergen hybrids - next generation vaccines for Fagales pollen immunotherapy. Clin Exp Allergy. 2014; 44: 438-449. Ref.: https://goo.gl/9mMJCs
  162. Wheeler AW, Woroniecki SR. Immunological adjuvants in allergy vaccines: Past, present future. Int Allergology. 2001; 50: 295-301. Ref.: https://goo.gl/jBGBMZ
  163. Apostolopoulos V, Thalhammer T, Tzakos AG, Stojanovska L. Targeting Antigens to Dendritic Cell Receptors for Vaccine Development. J Drug Deliv. 2013; 2013: 869718. Ref.: https://goo.gl/a4ox2r
  164. Kahlert H, Grage-Griebenow E, Stuwe HT, Cromwell O, Fiebig H. T Cell Reactivity with Allergoids: Influence of the type of APC. J Immunol. 2000; 165: 1807-1815. Ref.: https://goo.gl/Ymnx54
  165. Vlad G, Cortesini R, Suciu-Foca N. License to Heal: Bidirectional Interaction of Antigen-Specific Regulatory T Cells and Tolerogenic APC. J Immunol. 2005; 174: 5907-5914. Ref.: https://goo.gl/YHdjsz
  166. Salazar F, Sewell HF, Shakib F, Ghaemmaghami AM. The role of lectins in allergic sensitization and allergic disease. J Allergy Clin Immunol. 2013; 132: 27-36. Ref.: https://goo.gl/fU5z6h
  167. Figdor CG, van Kooyk Y, Adema GJ. C-type lectin receptors on dendritic cells and langerhans cells. Nat Rev Immunol. 2002; 2: 77-84. Ref.: https://goo.gl/sjqHYs
  168. Leroux-Roels G, Marchant A, Levy J, Van Damme P, Schwarz TF, et al. Impact of adjuvants on CD4+ T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial. Clin Immunol. 2016; 169: 16-27. Ref.: https://goo.gl/G9jYkn
  169. Burny W, Callegaro A, Bechtold V, Clement F, Delhaye S, et al. Different Adjuvants Induce Common Innate Pathways That Are Associated with Enhanced Adaptive Responses against a Model Antigen in Humans. Front Immunol. 2017; 8: 1-17. Ref.: https://goo.gl/3Q9Ktq
  170. Lipton MM, Freund J. The formation of complement fixing and neutralizing antibodies after the injection of inactivated rabies virus with adjuvants. J Immunol. 1950; 64: 297-303. Ref.: https://goo.gl/xVRGCs
  171. Kearney SC, Dziekiewicz M, Feleszko W. Immunoregulatory and immunostimulatory responses of bacterial lysates in respiratory infections and asthma. Ann Allergy Asthma Immunol. 2015; 114: 364-369. Ref.: https://goo.gl/z4dMdB
  172. Ahrens B, Quarcoo D, Buhner S, Matricardi PM, Hamelmann E. Oral Administration of Bacterial Lysates Attenuates Experimental Food Allergy. Int Arch Allergy Immunol. 2011; 156: 196-204. Ref.: https://goo.gl/5qMnVj
  173. Navarro S, Cossalter G, Chiavaroli C, Kanda A, Fleury S, et al. The oral administration of bacterial extracts prevents asthma via the recruitment of regulatory T cells to the airways. Mucosal Immunol. 2011; 4: 53-65. Ref.: https://goo.gl/BBA9j2
  174. Xu LZ, Yang LT, Qiu SQ, Yang G, Luo XQ, et al. Combination of specific allergen and probiotics induces specific regulatory B cells and enhances specific immunotherapy effect on allergic rhinitis. Oncotarget. 2016; 7: 54360-54369. Ref.: https://goo.gl/eW1XVH
  175. Glenny AT, Barr M. The precipitation of diphtheria toxoid by potash alum. J Pathol Bacteriol. 1931; 34: 131-138. Ref.: https://goo.gl/YrCVM7
  176. Sledge RF. Treatment of hay fever with alum-precipitated pollen extract. J Allergy. 1938; 9: 424.
  177. Mannhalter JW, Neychev HO, Zlabinger GJ, Ahmad R, Eibl MM. Modulation of the human immune response by the non-toxic and non-pyrogenic adjuvant aluminium hydroxide: effect on antigen uptake and antigen presentation. Clin Exp Immunol. 1985; 61: 143-151. Ref.: https://goo.gl/GmTjx9
  178. Jones SK, Lovell CR, Peachey RD. Delayed onset of inflammatory nodules following hay fever desensitization injections. Clin Exp Dermatol. 1988; 13: 376-378. Ref.: https://goo.gl/iX6zbF
  179. Castelain PY, Castelain M, Vervloet D, Garbe L, Mallet B. Sensitization to aluminium by aluminium-precipitated dust and pollen extracts. Contact Dermatitis. 1988; 19: 58-60. Ref.: https://goo.gl/aKTg4H
  180. Veien NK, Hattel T, Justesen O, Norholm A. Aluminium allergy. Contact Dermatitis. 1986; 15: 295-297. Ref.: https://goo.gl/N5B2hf
  181. Bondy SC, Campbell A. Oxidative and Inflammatory Properties of Aluminum: Possible Relevance in Alzheimer's Disease. In: Exley C, editor. Aluminium and Alzheimer's Disease. Amsterdam. 2001; 311-321.
  182. Pfaar O, Hohlfeld JM, Al-Kadah B, Hauswald B, Homey B, et al. Dose‐response relationship of a new Timothy grass pollen allergoid in comparison to a 6‐grass pollen allergoid. Clin Exp Allergy. 2017. Ref.: https://goo.gl/GgJQDz
  183. Kepil Özdemir S, Sin BA, Güloğlu D, İkincioğulları A, Gençtürk Z, et al. Short-term preseasonal Immunotherapy: is early clinical efficacy related to the Basophil Response? Int Arch Allergy Immunol. 2014; 164: 237-245. Ref.: https://goo.gl/kCQTeo
  184. Heydenreich B, Bellinghausen I, Lund L, Henmar H, Lund G, et al. Adjuvant effects of aluminium hydroxide-adsorbed allergens and allergoids – differences in vivo and in vitro. Clin Exp Immunol. 2014; 176: 310-319. Ref.: https://goo.gl/o9UFqb
  185. Wheeler AW, Whittall N, Spackman V, Moran DM. Adjuvant Properties of Hydrophobic Derivatives Prepared from L-Tyrosine. Int Arch Allergy Immunol. 1984; 75: 294-299. Ref.: https://goo.gl/MJWKBg
  186. Wheeler AW, Moran DM, Robins BE, Driscoll A. L-Tyrosine as an Immunological Adjuvant. Int Arch Allergy Immunol. 1982; 69: 113-119. Ref.: https://goo.gl/h92rNb
  187. Bell AJ, Heath MD, Hewings SJ, Skinner MA. The adsorption of allergoids and 3-O-desacyl-4'-monophosphoryl lipid A (MPLA®) to microcrystalline tyrosine (MCT) in formulations for use in allergy immunotherapy. J Inorg Biochem. 2015; 152: 147-153. Ref.: https://goo.gl/kxR6RL
  188. Baldrick P, Richardson D, Wheeler AW. Review of L-tyrosine confirming its safe human use as an adjuvant. J Appl Toxicol. 2002; 22: 333-344. Ref: https://goo.gl/KquyrL
  189. Roger A, Depreux N, Jurgens Y, Serra AT, Heath MD, et al. A novel microcrystalline tyrosine-adsorbed, mite-allergoid subcutaneous immunotherapy: 1-year follow-up report. Immunotherapy. 2016; 8: 1169-1174. Ref.: https://goo.gl/z1XEj3
  190. Sheng KC, Pouniotis DS, Wright MD, Kit Tang C, Lazoura E, et al. Mannan derivatives induce phenotypic and functional maturation of mouse dendritic cells. Immunology. 2006; 118: 372-383. Ref.: https://goo.gl/BgxzVZ
  191. Sirvent S, Soria I, Cirauqui C, Cases B, Manzano AI, et al. Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory Tcells through programmed death ligand 1. J Allergy Clin Immunol. 2016; 138: 558-567. Ref.: https://goo.gl/ZsG57N
  192. Beutler B, Rietschel ET. Innate immune sensing and its roots: the story of endotoxin. Nat Rev Immunol. 2003; 3: 169-176. Ref.: https://goo.gl/7TFKsA
  193. Ribi E, Parker R, Strain SM, Mizuno Y, Nowotny A, et al. Peptides as requirement for immunotherapy of the guinea-pig line-10 tumor with endotoxins. Cancer Immunol Immunother. 1979; 7: 43-58. Ref.: https://goo.gl/cgrkYC
  194. Casella CR, Mitchell TC. Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell mol life sci. 2008; 65: 3231-3240. Ref.: https://goo.gl/hpEUEL
  195. Baldrick P, Richardson D, Woroniecki SR, Lees B. Pollinex Quattro Ragweed: safety evaluation of a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL) for the treatment of ragweed pollen allergy. J Appl Toxicol. 2007; 27: 399-409. Ref.: https://goo.gl/tkkpqC
  196. Baldrick P, Richardson D, Wheeler AW. Safety evaluation of a glutaraldehyde modified tyrosine adsorbed house dust mite extract containing monophosphoryl lipid A (MPL®) adjuvant: a new allergy vaccine for dust mite allergy. Vaccine. 2001; 20: 737-743. Ref.: https://goo.gl/FRiUeu
  197. Drachenberg KJ, Wheeler AW, Stuebner P, Horak F. A well-tolerated grass pollen-specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid A, reduces allergic symptoms after only four preseasonal injections. Allergy. 2001; 56: 498-505. Ref.: https://goo.gl/Kf9F3Z
  198. 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. Allergologia et Immunopathologia. 2003; 31: 270-277. Ref.: https://goo.gl/ZaA64x
  199. Mothes N, Heinzkill M, Drachenberg KJ, Sperr WR, Krauth MT, 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. Ref.: https://goo.gl/LuyGYX
  200. Worm M, Ernst D, Kraller M, Babina M. The Impact on Allergy-Related Cells of a Birch Pollen Allergoid, with and without Monophosphoryl Lipid A, in Comparison with the Native Equivalent. Int Arch Allergy Immunol. 2017; 172: 20-26. Ref.: https://goo.gl/BrfCYj
  201. Ellis AK, Tsitoura DC, Quint D, Powley W, Lee LA. Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial. Clin Exp Allergy. 2017; 47: 1193-1203. Ref.: https://goo.gl/E7V3Zk
  202. Tighe H, Takabayashi K, Schwartz D, Marsden R, Beck L, et al. Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. Eur J Immunol. 2000; 30: 1939-1947. Ref.: https://goo.gl/MpDKrN
  203. Tighe H, Takabayashi K, Schwartz D, Van Nest G, Tuck S, 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. Ref.: https://goo.gl/9VSdBW
  204. Marshall JD, Abtahi S, Eiden JJ, Tuck S, Milley R, et al. Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes TH1 cytokine expression while downregulating TH2 cytokine expression in PBMCs from human patients with ragweed allergy. J Allergy Clin Immunol. 2001; 108:191-197. Ref.: https://goo.gl/q1BnQ9
  205. Creticos PS, Schroeder  JT, Hamilton  RG, Balcer-Whaley  SL, Khattignavong  AP, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006; 355: 1445-1455. Ref.: https://goo.gl/qFhJCt
  206. Senti G, Johansen P, Haug S, Bull C, Gottschaller C, et al. 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. Ref.: https://goo.gl/LH9iye
  207. Levy JH. Anti-inflammatory strategies and hemostatic agents: old Drugs, new Ideas. Hematol Oncol Clin North Am. 2007; 21: 89-101. Ref.: https://goo.gl/4ZiRhk
  208. Alkjaersig N, Fletcher AP, Sherry S. xi-Aminocaproic acid: an inhibitor of plasminogen activation. J Biol Chem. 1959; 234: 832-837. Ref.: https://goo.gl/KCE9bW
  209. Camões S, Mendonça I, Marinho JB. Treatment for desensitizing allergic disorders associated with oral epsilon aminocaproic acid. Patologia Geral Brazil. 1971; 56: 87-93.
  210. Petrarca C, Clemente E, Amato V, Gatta A, Cortese S, et al. Vitamin D3 improves the effects of low dose Der p 2 allergoid treatment in Der p 2 sensitized BALB/c mice. Clin Mol Allergy. 2016; 14: 7. Ref.: https://goo.gl/U8rRhM
  211. Kirchner B, Pfaffl MW, Dumpler J, von Mutius E, Ege MJ. microRNA in native and processed cow's milk and its implication for the farm milk effect on asthma. J Allergy Clin Immunol. 2016; 137: 1893-1895. Ref.: https://goo.gl/vpcjAa
  212. Kosaka N, Izumi H, Sekine K, Ochiya T. microRNA as a new immune-regulatory agent in breast milk. Silence. 2010; 1: 7. Ref.: https://goo.gl/cQ3Agt
  213. Kirchner B, Pfaffl MW, Dumpler J, von Mutius E, Ege MJ. MicroRNA in native and processed cow's milk and its implication for the farm milk effect on asthma. J Allergy Clin Immunol. 2016; 137: 1893-1895. Ref.: https://goo.gl/ghHiR9
  214. Baier SR, Nguyen C, Xie F, Wood JR, Zempleni J. MicroRNAs Are Absorbed in Biologically Meaningful Amounts from Nutritionally Relevant Doses of Cow Milk and Affect Gene Expression in Peripheral Blood Mononuclear Cells, HEK-293 Kidney Cell Cultures, and Mouse Livers. J Nutr. 2014; 144: 1495-1500. Ref.: https://goo.gl/jw262K
  215. Melnik BC, John SM, Schmitz G. Milk: An epigenetic inducer of FoxP3 expression. J Allergy Clin Immunol. 2017; 138: 937-938. Ref.: https://goo.gl/oLGebX
  216. Caubet JC, Bencharitiwong R, Ross A, Sampson HA, Berin MC, et al. Humoral and cellular responses to casein in patients with food protein-induced enterocolitis to cow's milk. J Allergy Clin Immunol. 2017; 139: 572-583. Ref.: https://goo.gl/Q2HWcD
  217. Krook H, Hagberg A, Song Z, Landegren U, Wennberg L, et al. A distinct Th1 Immune Response Precedes the Described Th2 Response in Islet Xenograft Rejection. Diabetes. 2002; 51: 79-86. Ref.: https://goo.gl/mS1eP1

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