Seminars in Immunopathology

, Volume 34, Issue 5, pp 689–702 | Cite as

Immunological mechanisms for desensitization and tolerance in food allergy

  • Rima Rachid
  • Dale T. Umetsu


Food allergy is a major public health concern in westernized countries, estimated to affect 5 % of children and 3–4 % of adults. Allergen-specific immunotherapy for food allergy is currently being actively evaluated, but is still experimental. The optimal protocol, in terms of the route of administration of the food, target maintenance dose, and duration of maintenance therapy, and the optimal patient for these procedures are still being worked out. The mechanisms underlying successful food desensitization are also unclear, in part, because there is no standard immunotherapy protocol. The mechanisms involved, however, may include mast cell and basophil suppression, development of food-specific IgG4 antibodies, reduction in the food-specific IgE/IgG4 ratio, up-regulation and expansion of natural or inducible regulatory T cells, a skewing from a Th2 to a Th1 profile, and the development of anergy and/or deletion in antigen-specific cells. Additional studies are required to elucidate and understand these mechanisms by which desensitization and tolerance are achieved, which may reveal valuable biomarkers for evaluating and following food allergic patients on immunotherapy.


Food allergy Immunotherapy Desensitization Tolerance 



Double-blind placebo-controlled food challenge


Inducible regulatory T cells




Monoclonal antibody


Natural regulatory T cells


Oral food challenge


Oral immunotherapy


Secretory IgA


Sublingual immunotherapy


Skin prick test


Spleen tyrosine kinase


Regulatory T cells


  1. 1.
    Sicherer SH, Sampson HA (2010) Food allergy. J Allergy Clin Immunol 125:S116–125PubMedCrossRefGoogle Scholar
  2. 2.
    Branum AM, Lukacs SL (2008) Food allergy among U.S. children: trends in prevalence and hospitalizations. NCHS Data Brief: 1–8Google Scholar
  3. 3.
    Lee LA, Burks AW (2006) Food allergies: prevalence, molecular characterization, and treatment/prevention strategies. Annu Rev Nutr 26:539–565PubMedCrossRefGoogle Scholar
  4. 4.
    Sicherer SH, Munoz-Furlong A, Sampson HA (2003) Prevalence of peanut and tree nut allergy in the United States determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol 112:1203–1207PubMedCrossRefGoogle Scholar
  5. 5.
    Grundy J, Matthews S, Bateman B, Dean T, Arshad SH (2002) Rising prevalence of allergy to peanut in children: data from 2 sequential cohorts. J Allergy Clin Immunol 110:784–789PubMedCrossRefGoogle Scholar
  6. 6.
    Skripak JM, Matsui EC, Mudd K, Wood RA (2007) The natural history of IgE-mediated cow’s milk allergy. J Allergy Clin Immunol 120:1172–1177PubMedCrossRefGoogle Scholar
  7. 7.
    Jarvinen KM, Beyer K, Vila L, Bardina L, Mishoe M, Sampson HA (2007) Specificity of IgE antibodies to sequential epitopes of hen's egg ovomucoid as a marker for persistence of egg allergy. Allergy 62:758–765PubMedCrossRefGoogle Scholar
  8. 8.
    Skolnick HS, Conover-Walker MK, Koerner CB, Sampson HA, Burks W, Wood RA (2001) The natural history of peanut allergy. J Allergy Clin Immunol 107:367–374PubMedCrossRefGoogle Scholar
  9. 9.
    Bock SA, Munoz-Furlong A, Sampson HA (2001) Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 107:191–193PubMedCrossRefGoogle Scholar
  10. 10.
    Bock SA, Munoz-Furlong A, Sampson HA (2007) Further fatalities caused by anaphylactic reactions to food, 2001-2006. J Allergy Clin Immunol 119:1016–1018PubMedCrossRefGoogle Scholar
  11. 11.
    Sicherer SH, Noone SA, Munoz-Furlong A (2001) The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol 87:461–464PubMedCrossRefGoogle Scholar
  12. 12.
    Cummings AJ, Knibb RC, King RM, Lucas JS (2010) The psychosocial impact of food allergy and food hypersensitivity in children, adolescents and their families: a review. Allergy 65:933–945PubMedCrossRefGoogle Scholar
  13. 13.
    Sicherer SH, Furlong TJ, DeSimone J, Sampson HA (2001) The US Peanut and Tree Nut Allergy Registry: characteristics of reactions in schools and day care. J Pediatr 138:560–565PubMedCrossRefGoogle Scholar
  14. 14.
    Furlong TJ, DeSimone J, Sicherer SH (2001) Peanut and tree nut allergic reactions in restaurants and other food establishments. J Allergy Clin Immunol 108:867–870PubMedCrossRefGoogle Scholar
  15. 15.
    Boyano-Martinez T, Garcia-Ara C, Pedrosa M, Diaz-Pena JM, Quirce S (2009) Accidental allergic reactions in children allergic to cow's milk proteins. J Allergy Clin Immunol 123:883–888PubMedCrossRefGoogle Scholar
  16. 16.
    Vander Leek TK, Liu AH, Stefanski K, Blacker B, Bock SA (2000) The natural history of peanut allergy in young children and its association with serum peanut-specific IgE. J Pediatr 137:749–755PubMedCrossRefGoogle Scholar
  17. 17.
    Akdis CA, Akdis M (2011) Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 127:18–27, quiz 8-9PubMedCrossRefGoogle Scholar
  18. 18.
    Fujita H, Soyka MB, Akdis M, Akdis CA (2012) Mechanisms of allergen-specific immunotherapy. Clin Transl Allergy 2:2PubMedCrossRefGoogle Scholar
  19. 19.
    Nelson HS, Lahr J, Rule R, Bock A, Leung D (1997) Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol 99:744–751PubMedCrossRefGoogle Scholar
  20. 20.
    Fernandez-Rivas M, Garrido Fernandez S, Nadal JA, Diaz de Durana MD, Garcia BE, Gonzalez-Mancebo E, Martin S, Barber D, Rico P, Tabar AI (2009) Randomized double-blind, placebo-controlled trial of sublingual immunotherapy with a Pru p 3 quantified peach extract. Allergy 64:876–883PubMedCrossRefGoogle Scholar
  21. 21.
    Pereira C, Bartolome B, Asturias JA, Ibarrola I, Tavares B, Loureiro G, Machado D, Chieira C (2009) Specific sublingual immunotherapy with peach LTP (Pru p 3). One year treatment: a case report. Cases J 2:6553PubMedCrossRefGoogle Scholar
  22. 22.
    Garcia BE, Gonzalez-Mancebo E, Barber D, Martin S, Tabar AI, Diaz de Durana AM, Garrido-Fernandez S, Salcedo G, Rico P, Fernandez-Rivas M. Sublingual immunotherapy in peach allergy: monitoring molecular sensitizations and reactivity to apple fruit and Platanus pollen. J Investig Allergol Clin Immunol 20: 514–520Google Scholar
  23. 23.
    Kerzl R, Simonowa A, Ring J, Ollert M, Mempel M (2007) Life-threatening anaphylaxis to kiwi fruit: protective sublingual allergen immunotherapy effect persists even after discontinuation. J Allergy Clin Immunol 119:507–8PubMedCrossRefGoogle Scholar
  24. 24.
    Mempel M, Rakoski J, Ring J, Ollert M (2003) Severe anaphylaxis to kiwi fruit: immunologic changes related to successful sublingual allergen immunotherapy. J Allergy Clin Immunol 111:1406–9PubMedCrossRefGoogle Scholar
  25. 25.
    Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella R, Castello JV, Alonso R, de Mateo JA, Cerda-Trias T, San Miguel-Moncin Mdel M, Monzon S, Garcia M, Palacios R, Cistero-Bahima A (2005) Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol 116:1073–9PubMedCrossRefGoogle Scholar
  26. 26.
    Kim EH, Bird JA, Kulis M, Laubach S, Pons L, Shreffler W, Steele P, Kamilaris J, Vickery B, Burks AW. Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol 127: 640–6e1Google Scholar
  27. 27.
    Enrique E, Malek T, Pineda F, Palacios R, Bartra J, Tella R, Basagana M, Alonso R, Cistero-Bahima A (2008) Sublingual immunotherapy for hazelnut food allergy: a follow-up study. Ann Allergy Asthma Immunol 100:283–4PubMedCrossRefGoogle Scholar
  28. 28.
    Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, Schroeder JT, Hamilton RG, Boden S, Steele P, Driggers S, Burks AW, Wood RA. The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol 129: 448–55, 55 e1–5Google Scholar
  29. 29.
    Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, Hiegel A, Kamilaris J, Carlisle S, Yue X, Kulis M, Pons L, Vickery B, Burks AW. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol 127: 654–660Google Scholar
  30. 30.
    Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, Shreffler WG, Steele P, Henry KA, Adair M, Francis JM, Durham S, Vickery BP, Zhong X, Burks AW (2009) Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol 124(292–300):e1–97Google Scholar
  31. 31.
    Meglio P, Bartone E, Plantamura M, Arabito E, Giampietro PG (2004) A protocol for oral desensitization in children with IgE-mediated cow's milk allergy. Allergy 59:980–7PubMedCrossRefGoogle Scholar
  32. 32.
    Clark AT, Islam S, King Y, Deighton J, Anagnostou K, Ewan PW (2009) Successful oral tolerance induction in severe peanut allergy. Allergy 64:1218–20PubMedCrossRefGoogle Scholar
  33. 33.
    Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT. Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy. J Allergy Clin Immunol 127: 1622–1624Google Scholar
  34. 34.
    Longo G, Barbi E, Berti I, Meneghetti R, Pittalis A, Ronfani L, Ventura A (2008) Specific oral tolerance induction in children with very severe cow's milk-induced reactions. J Allergy Clin Immunol 121:343–7PubMedCrossRefGoogle Scholar
  35. 35.
    Itoh N, Itagaki Y, Kurihara K. Rush specific oral tolerance induction in school-age children with severe egg allergy: one year follow up. Allergol Int 59: 43–51Google Scholar
  36. 36.
    Buchanan AD, Green TD, Jones SM, Scurlock AM, Christie L, Althage KA, Steele PH, Pons L, Helm RM, Lee LA, Burks AW (2007) Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol 119:199–205PubMedCrossRefGoogle Scholar
  37. 37.
    Staden U, Blumchen K, Blankenstein N, Dannenberg N, Ulbricht H, Dobberstein K, Ziegert M, Niggemann B, Wahn U, Beyer K (2008) Rush oral immunotherapy in children with persistent cow's milk allergy. J Allergy Clin Immunol 122:418–9PubMedCrossRefGoogle Scholar
  38. 38.
    Blumchen K, Ulbricht H, Staden U, Dobberstein K, Beschorner J, de Oliveira LC, Shreffler WG, Sampson HA, Niggemann B, Wahn U, Beyer K. Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy Clin Immunol 126: 83–91 e1Google Scholar
  39. 39.
    Dupont C, Kalach N, Soulaines P, Legoue-Morillon S, Piloquet H, Benhamou PH. Cow's milk epicutaneous immunotherapy in children: a pilot trial of safety, acceptability, and impact on allergic reactivity. J Allergy Clin Immunol 125: 1165–1167Google Scholar
  40. 40.
    Skripak JM, Nash SD, Rowley H, Brereton NH, Oh S, Hamilton RG, Matsui EC, Burks AW, Wood RA (2008) A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy. J Allergy Clin Immunol 122:1154–60PubMedCrossRefGoogle Scholar
  41. 41.
    Vickery BP, Pons L, Kulis M, Steele P, Jones SM, Burks AW. Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance. Ann Allergy Asthma Immunol 105: 444–450Google Scholar
  42. 42.
    Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K (2007) Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 62:1261–1269PubMedCrossRefGoogle Scholar
  43. 43.
    Rolinck-Werninghaus C, Staden U, Mehl A, Hamelmann E, Beyer K, Niggemann B (2005) Specific oral tolerance induction with food in children: transient or persistent effect on food allergy? Allergy 60:1320–1322PubMedCrossRefGoogle Scholar
  44. 44.
    Vickery BP, Burks W. Oral immunotherapy for food allergy. Curr Opin Pediatr 22: 765–770Google Scholar
  45. 45.
    Nadeau KC, Kohli A, Iyengar S, DeKruyff RH, Umetsu DT. Oral immunotherapy and anti-IgE antibody-adjunctive treatment for food allergy. Immunol Allergy Clin North Am 32: 111–133Google Scholar
  46. 46.
    Nowak-Wegrzyn A, Sampson HA. Future therapies for food allergies. J Allergy Clin Immunol 127: 558–573; quiz 74–75Google Scholar
  47. 47.
    Meglio P, Giampietro PG, Gianni S, Galli E (2008) Oral desensitization in children with immunoglobulin E-mediated cow's milk allergy—follow-up at 4 yr and 8 months. Pediatr Allergy Immunol 19:412–419PubMedCrossRefGoogle Scholar
  48. 48.
    Vickery BP, Pons L, Kulis M, Steele P, Jones SM, Burks AW (2010) Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance. Ann Allergy Asthma Immunol 105:444–450PubMedCrossRefGoogle Scholar
  49. 49.
    Blumchen K, Ulbricht H, Staden U, Dobberstein K, Beschorner J, de Oliveira LC, Shreffler WG, Sampson HA, Niggemann B, Wahn U, Beyer K (2010) Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy Clin Immunol 126(83–91):e1PubMedGoogle Scholar
  50. 50.
    Keet CA, Frischmeyer-Guerrerio PA, Thyagarajan A, Schroeder JT, Hamilton RG, Boden S, Steele P, Driggers S, Burks AW, Wood RA (2012) The safety and efficacy of sublingual and oral immunotherapy for milk allergy. J Allergy Clin Immunol 129:448–455, 55 e1–5PubMedCrossRefGoogle Scholar
  51. 51.
    Varshney P, Steele PH, Vickery BP, Bird JA, Thyagarajan A, Scurlock AM, Perry TT, Jones SM, Burks AW (2009) Adverse reactions during peanut oral immunotherapy home dosing. J Allergy Clin Immunol 124:1351–1352PubMedCrossRefGoogle Scholar
  52. 52.
    Lack G Update on risk factors for food allergy. J Allergy Clin Immunol 129: 1187–1197Google Scholar
  53. 53.
    Larche M, Akdis CA, Valenta R (2006) Immunological mechanisms of allergen-specific immunotherapy. Nat Rev Immunol 6:761–771PubMedCrossRefGoogle Scholar
  54. 54.
    Berin MC, Shreffler WG (2008) T(H)2 adjuvants: implications for food allergy. J Allergy Clin Immunol 121:1311–1320, quiz 21-2PubMedCrossRefGoogle Scholar
  55. 55.
    Chatila TA, Li N, Garcia-Lloret M, Kim HJ, Nel AE (2008) T-cell effector pathways in allergic diseases: transcriptional mechanisms and therapeutic targets. J Allergy Clin Immunol 121:812–823, quiz 24-5PubMedCrossRefGoogle Scholar
  56. 56.
    Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E (2009) IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol 123:1244–1252, e2PubMedCrossRefGoogle Scholar
  57. 57.
    Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA (2003) IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 33:1205–1214PubMedCrossRefGoogle Scholar
  58. 58.
    Francis JN, Till SJ, Durham SR (2003) Induction of IL-10 + CD4 + CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol 111:1255–1261PubMedCrossRefGoogle Scholar
  59. 59.
    Akdis M, Blaser K, Akdis CA (2005) T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J Allergy Clin Immunol 116:961–968, quiz 9PubMedCrossRefGoogle Scholar
  60. 60.
    Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA (2010) Role of Treg in immune regulation of allergic diseases. Eur J Immunol 40:1232–1240PubMedCrossRefGoogle Scholar
  61. 61.
    Gri G, Piconese S, Frossi B, Manfroi V, Merluzzi S, Tripodo C, Viola A, Odom S, Rivera J, Colombo MP, Pucillo CE (2008) CD4 + CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 29:771–781PubMedCrossRefGoogle Scholar
  62. 62.
    Kearley J, Barker JE, Robinson DS, Lloyd CM (2005) Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4 + CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 202:1539–1547PubMedCrossRefGoogle Scholar
  63. 63.
    Kearley J, Robinson DS, Lloyd CM (2008) CD4 + CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. J Allergy Clin Immunol 122:617–624, e6PubMedCrossRefGoogle Scholar
  64. 64.
    Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M (2008) Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy 63:1455–1463PubMedCrossRefGoogle Scholar
  65. 65.
    Lin W, Truong N, Grossman WJ, Haribhai D, Williams CB, Wang J, Martin MG, Chatila TA (2005) Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. J Allergy Clin Immunol 116:1106–1115PubMedCrossRefGoogle Scholar
  66. 66.
    Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106:R75–81PubMedCrossRefGoogle Scholar
  67. 67.
    Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, Umetsu DT, Rudensky AY. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482: 395–399Google Scholar
  68. 68.
    Duan W, So T, Mehta AK, Choi H, Croft M (2011) Inducible CD4 + LAP + Foxp3- regulatory T cells suppress allergic inflammation. J Immunol 187:6499–6507PubMedCrossRefGoogle Scholar
  69. 69.
    Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115:1923–1933PubMedCrossRefGoogle Scholar
  70. 70.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov, II, Umesaki Y, Itoh K, Honda K. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331: 337–41Google Scholar
  71. 71.
    Radulovic S, Jacobson MR, Durham SR, Nouri-Aria KT (2008) Grass pollen immunotherapy induces Foxp3-expressing CD4+ CD25+ cells in the nasal mucosa. J Allergy Clin Immunol 121:1467–1472, 72 e1PubMedCrossRefGoogle Scholar
  72. 72.
    Allam JP, Wurtzen PA, Reinartz M, Winter J, Vrtala S, Chen KW, Valenta R, Wenghoefer M, Appel T, Gros E, Niederhagen B, Bieber T, Lund K, Novak N (2010) Phl p 5 resorption in human oral mucosa leads to dose-dependent and time-dependent allergen binding by oral mucosal Langerhans cells, attenuates their maturation, and enhances their migratory and TGF-beta1 and IL-10-producing properties. J Allergy Clin Immunol 126:638–645, e1PubMedCrossRefGoogle Scholar
  73. 73.
    Taylor A, Akdis M, Joss A, Akkoc T, Wenig R, Colonna M, Daigle I, Flory E, Blaser K, Akdis CA (2007) IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1. J Allergy Clin Immunol 120:76–83PubMedCrossRefGoogle Scholar
  74. 74.
    Marshall JS, Leal-Berumen I, Nielsen L, Glibetic M, Jordana M (1996) Interleukin (IL)-10 inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. J Clin Invest 97:1122–1128PubMedCrossRefGoogle Scholar
  75. 75.
    Schandene L, Alonso-Vega C, Willems F, Gerard C, Delvaux A, Velu T, Devos R, de Boer M, Goldman M (1994) B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10. J Immunol 152:4368–4374PubMedGoogle Scholar
  76. 76.
    Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4 + CD25- naive T cells to CD4 + CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886PubMedCrossRefGoogle Scholar
  77. 77.
    Liu YJ (2006) Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med 203:269–273PubMedCrossRefGoogle Scholar
  78. 78.
    Lee EB, Kim KW, Hong JY, Jee HM, Sohn MH, Kim KE (2010) Increased serum thymic stromal lymphopoietin in children with atopic dermatitis. Pediatr Allergy Immunol 21:e457–460PubMedCrossRefGoogle Scholar
  79. 79.
    Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, Wherry EJ, Jessup HK, Siegel LA, Kambayashi T, Dudek EC, Kubo M, Cianferoni A, Spergel JM, Ziegler SF, Comeau MR, Artis D. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477: 229–233Google Scholar
  80. 80.
    Zhu Z, Oh MH, Yu J, Liu YJ, Zheng T (2011) The role of TSLP in IL-13-induced atopic march. Sci Rep 1:23PubMedCrossRefGoogle Scholar
  81. 81.
    Pushparaj PN, Tay HK, H'Ng SC, Pitman N, Xu D, McKenzie A, Liew FY, Melendez AJ (2009) The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci U S A 106:9773–9778PubMedCrossRefGoogle Scholar
  82. 82.
    Koyasu S, Moro K, Tanabe M, Takeuchi T (2010) Natural helper cells: a new player in the innate immune response against helminth infection. Adv Immunol 108:21–44PubMedCrossRefGoogle Scholar
  83. 83.
    Koyasu S, Moro K (2011) Innate Th2-type immune responses and the natural helper cell, a newly identified lymphocyte population. Curr Opin Allergy Clin Immunol 11:109–114PubMedCrossRefGoogle Scholar
  84. 84.
    Chang YJ, Kim HY, Albacker LA, Baumgarth N, McKenzie AN, Smith DE, Dekruyff RH, Umetsu DT. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12: 631–638Google Scholar
  85. 85.
    Allakhverdi Z, Comeau MR, Jessup HK, Delespesse G (2009) Thymic stromal lymphopoietin as a mediator of crosstalk between bronchial smooth muscles and mast cells. J Allergy Clin Immunol 123(958–60):e2PubMedGoogle Scholar
  86. 86.
    Van Ree R, Van Leeuwen WA, Dieges PH, Van Wijk RG, De Jong N, Brewczyski PZ, Kroon AM, Schilte PP, Tan KY, Simon-Licht IF, Roberts AM, Stapel SO, Aalberse RC (1997) Measurement of IgE antibodies against purified grass pollen allergens (Lol p 1, 2, 3 and 5) during immunotherapy. Clin Exp Allergy 27:68–74PubMedCrossRefGoogle Scholar
  87. 87.
    Gleich GJ, Zimmermann EM, Henderson LL, Yunginger JW (1982) Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study. J Allergy Clin Immunol 70:261–271PubMedCrossRefGoogle Scholar
  88. 88.
    Eberlein-Konig B, Ullmann S, Thomas P, Przybilla B (1995) Tryptase and histamine release due to a sting challenge in bee venom allergic patients treated successfully or unsuccessfully with hyposensitization. Clin Exp Allergy 25:704–712PubMedCrossRefGoogle Scholar
  89. 89.
    Jutel M, Muller UR, Fricker M, Rihs S, Pichler WJ, Dahinden C (1996) Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils. Clin Exp Allergy 26:1112–1118PubMedCrossRefGoogle Scholar
  90. 90.
    Plewako H, Wosinska K, Arvidsson M, Bjorkander J, Skov PS, Hakansson L, Rak S (2006) Basophil interleukin 4 and interleukin 13 production is suppressed during the early phase of rush immunotherapy. Int Arch Allergy Immunol 141:346–353PubMedCrossRefGoogle Scholar
  91. 91.
    Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, Hiegel A, Kamilaris J, Carlisle S, Yue X, Kulis M, Pons L, Vickery B, Burks AW (2011) A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol 127:654–660PubMedCrossRefGoogle Scholar
  92. 92.
    Bedoret D, Singh AK, Shaw V, Hoyte EG, Hamilton R, Dekruyff RH, Schneider LC, Nadeau KC, Umetsu DT. Changes in antigen-specific T-cell number and function during oral desensitization in cow's milk allergy enabled with omalizumab. Mucosal Immunol 5: 267–276Google Scholar
  93. 93.
    Scadding G, Durham S (2009) Mechanisms of sublingual immunotherapy. J Asthma 46:322–334PubMedCrossRefGoogle Scholar
  94. 94.
    Allam JP, Peng WM, Appel T, Wenghoefer M, Niederhagen B, Bieber T, Berge S, Novak N (2008) Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells. J Allergy Clin Immunol 121:368–374, e1PubMedCrossRefGoogle Scholar
  95. 95.
    Allam JP, Novak N, Fuchs C, Asen S, Berge S, Appel T, Geiger E, Kochan JP, Bieber T (2003) Characterization of dendritic cells from human oral mucosa: a new Langerhans' cell type with high constitutive FcepsilonRI expression. J Allergy Clin Immunol 112:141–148PubMedCrossRefGoogle Scholar
  96. 96.
    Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK, Staple SQ, Aalberse RC, Till SJ, Durham SR (2004) Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol 172:3252–3259PubMedGoogle Scholar
  97. 97.
    Zemann B, Schwaerzler C, Griot-Wenk M, Nefzger M, Mayer P, Schneider H, de Weck A, Carballido JM, Liehl E (2003) Oral administration of specific antigens to allergy-prone infant dogs induces IL-10 and TGF-beta expression and prevents allergy in adult life. J Allergy Clin Immunol 111:1069–1075PubMedGoogle Scholar
  98. 98.
    Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F, Groux H (2003) Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity 18:605–617PubMedCrossRefGoogle Scholar
  99. 99.
    Bottcher MF, Jenmalm MC (2002) Breastfeeding and the development of atopic disease during childhood. Clin Exp Allergy 32:159–161PubMedCrossRefGoogle Scholar
  100. 100.
    Scadding GW, Shamji MH, Jacobson MR, Lee DI, Wilson D, Lima MT, Pitkin L, Pilette C, Nouri-Aria K, Durham SR. Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells. Clin Exp Allergy 40: 598–606Google Scholar
  101. 101.
    Kulis M, Saba K, Kim EH, Bird JA, Kamilaris N, Vickery BP, Staats H, Burks AW. Increased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy. J Allergy Clin Immunol 129: 1159–1162Google Scholar
  102. 102.
    Itoh N, Itagaki Y, Kurihara K (2010) Rush specific oral tolerance induction in school-age children with severe egg allergy: one year follow up. Allergol Int 59:43–51PubMedCrossRefGoogle Scholar
  103. 103.
    Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O (2005) Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol 116:608–613PubMedCrossRefGoogle Scholar
  104. 104.
    Reisinger J, Horak F, Pauli G, van Hage M, Cromwell O, Konig F, Valenta R, Niederberger V (2005) Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity. J Allergy Clin Immunol 116:347–354PubMedCrossRefGoogle Scholar
  105. 105.
    Golden DB, Meyers DA, Kagey-Sobotka A, Valentine MD, Lichtenstein LM (1982) Clinical relevance of the venom-specific immunoglobulin G antibody level during immunotherapy. J Allergy Clin Immunol 69:489–93PubMedCrossRefGoogle Scholar
  106. 106.
    Muller U, Helbling A, Bischof M (1989) Predictive value of venom-specific IgE, IgG and IgG subclass antibodies in patients on immunotherapy with honey bee venom. Allergy 44:412–418PubMedCrossRefGoogle Scholar
  107. 107.
    Schroeder HW Jr, Cavacini L (2010) Structure and function of immunoglobulins. J Allergy Clin Immunol 125:S41–52PubMedCrossRefGoogle Scholar
  108. 108.
    Wachholz PA, Durham SR (2004) Mechanisms of immunotherapy: IgG revisited. Curr Opin Allergy Clin Immunol 4:313–318PubMedCrossRefGoogle Scholar
  109. 109.
    Till SJ, Francis JN, Nouri-Aria K, Durham SR (2004) Mechanisms of immunotherapy. J Allergy Clin Immunol 113:1025–1034, quiz 35PubMedCrossRefGoogle Scholar
  110. 110.
    Uermosi C, Beerli RR, Bauer M, Manolova V, Dietmeier K, Buser RB, Kundig TM, Saudan P, Bachmann MF (2010) Mechanisms of allergen-specific desensitization. J Allergy Clin Immunol 126:375–383PubMedCrossRefGoogle Scholar
  111. 111.
    Carballido JM, Carballido-Perrig N, Kagi MK, Meloen RH, Wuthrich B, Heusser CH, Blaser K (1993) T cell epitope specificity in human allergic and nonallergic subjects to bee venom phospholipase A2. J Immunol 150:3582–3591PubMedGoogle Scholar
  112. 112.
    Shreffler WG, Wanich N, Moloney M, Nowak-Wegrzyn A, Sampson HA (2009) Association of allergen-specific regulatory T cells with the onset of clinical tolerance to milk protein. J Allergy Clin Immunol 123:43–52, e7PubMedCrossRefGoogle Scholar
  113. 113.
    Weiner HL (2000) Oral tolerance, an active immunologic process mediated by multiple mechanisms. J Clin Invest 106:935–7PubMedCrossRefGoogle Scholar
  114. 114.
    Hoyne GF, Tan K, Corsin-Jimenez M, Wahl K, Stewart M, Howie SE, Lamb JR (2000) Immunological tolerance to inhaled antigen. Am J Respir Crit Care Med 162:S169–174PubMedGoogle Scholar
  115. 115.
    Nadeau KC, Schneider LC, Hoyte L, Borras I, Umetsu DT (2011) Rapid oral desensitization in combination with omalizumab therapy in patients with cow's milk allergy. J Allergy Clin Immunol 127:1622–1624PubMedCrossRefGoogle Scholar
  116. 116.
    MacGlashan DW Jr, Bochner BS, Adelman DC, Jardieu PM, Togias A, McKenzie-White J, Sterbinsky SA, Hamilton RG, Lichtenstein LM (1997) Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 158:1438–1445PubMedGoogle Scholar
  117. 117.
    Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125:S73–80PubMedCrossRefGoogle Scholar
  118. 118.
    Kitaura J, Song J, Tsai M, Asai K, Maeda-Yamamoto M, Mocsai A, Kawakami Y, Liu FT, Lowell CA, Barisas BG, Galli SJ, Kawakami T (2003) Evidence that IgE molecules mediate a spectrum of effects on mast cell survival and activation via aggregation of the FcepsilonRI. Proc Natl Acad Sci U S A 100:12911–12916PubMedCrossRefGoogle Scholar
  119. 119.
    Corren J, Shapiro G, Reimann J, Deniz Y, Wong D, Adelman D, Togias A (2008) Allergen skin tests and free IgE levels during reduction and cessation of omalizumab therapy. J Allergy Clin Immunol 121:506–511PubMedCrossRefGoogle Scholar
  120. 120.
    Noga O, Hanf G, Kunkel G (2003) Immunological and clinical changes in allergic asthmatics following treatment with omalizumab. Int Arch Allergy Immunol 131:46–52PubMedCrossRefGoogle Scholar
  121. 121.
    Hill DA, Siracusa MC, Abt MC, Kim BS, Kobuley D, Kubo M, Kambayashi T, Larosa DF, Renner ED, Orange JS, Bushman FD, Artis D (2012) Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat Med 18:538–546PubMedCrossRefGoogle Scholar
  122. 122.
    Turcanu V, Maleki SJ, Lack G (2003) Characterization of lymphocyte responses to peanuts in normal children, peanut-allergic children, and allergic children who acquired tolerance to peanuts. J Clin Invest 111:1065–1072PubMedGoogle Scholar
  123. 123.
    Nagata S, McKenzie C, Pender SL, Bajaj-Elliott M, Fairclough PD, Walker-Smith JA, Monteleone G, MacDonald TT (2000) Human Peyer's patch T cells are sensitized to dietary antigen and display a Th cell type 1 cytokine profile. J Immunol 165:5315–5321PubMedGoogle Scholar
  124. 124.
    Faria AM, Weiner HL (2005) Oral tolerance. Immunol Rev 206:232–59PubMedCrossRefGoogle Scholar
  125. 125.
    Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M (2008) In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med 205:2887–2898PubMedCrossRefGoogle Scholar
  126. 126.
    Aslam A, Chan H, Warrell DA, Misbah S, Ogg GS. Tracking antigen-specific T-cells during clinical tolerance induction in humans. PLoS One 5: e11028Google Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Karp Laboratories, Division of Immunology and AllergyBoston Children’s HospitalBostonUSA
  2. 2.Harvard Medical SchoolBostonUSA

Personalised recommendations