Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Allergen immunotherapy for allergic disease: Therapeutic mechanisms

Mübeccel Akdis, MD, PhD
Section Editor
Peter S Creticos, MD
Deputy Editor
Anna M Feldweg, MD


Allergen immunotherapy (AIT) is the only disease-modifying treatment available for several common allergic diseases. Subcutaneous immunotherapy (SCIT) is the best studied form of AIT and is effective for allergic rhinitis and rhinoconjunctivitis, allergic asthma, and Hymenoptera venom allergy. SCIT involves the repeated subcutaneous injection of increasing amounts of allergen beginning with very small doses of allergen and gradually increasing to higher doses. Another popular method of AIT involves sublingual administration in the form of dissolvable tablets or extracts. This topic will discuss the known immunologic changes that occur during AIT. Other topics related to AIT are found separately:

(See "Subcutaneous immunotherapy for allergic disease: Indications and efficacy".)

(See "Sublingual immunotherapy for allergic rhinoconjunctivitis and asthma".)

(See "SCIT: Standard schedules, administration techniques, and monitoring".)

(See "SCIT: Preparation of allergen extracts for therapeutic use".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Sep 26, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. J Allergy Clin Immunol 2014; 133:621.
  2. Allam JP, Novak N. Immunological mechanisms of sublingual immunotherapy. Curr Opin Allergy Clin Immunol 2014; 14:564.
  3. Nelson HS, Makatsori M, Calderon MA. Subcutaneous Immunotherapy and Sublingual Immunotherapy: Comparative Efficacy, Current and Potential Indications, and Warnings--United States Versus Europe. Immunol Allergy Clin North Am 2016; 36:13.
  4. Creticos PS. Immunotherapy with allergens. JAMA 1992; 268:2834.
  5. Creticos PS, Adkinson NF Jr, Kagey-Sobotka A, et al. Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy. J Clin Invest 1985; 76:2247.
  6. Iliopoulos O, Proud D, Adkinson NF Jr, et al. Effects of immunotherapy on the early, late, and rechallenge nasal reaction to provocation with allergen: changes in inflammatory mediators and cells. J Allergy Clin Immunol 1991; 87:855.
  7. Maintz L, Bussmann C, Bieber T, Novak N. Contribution of histamine metabolism to tachyphylaxis during the buildup phase of rush immunotherapy. J Allergy Clin Immunol 2009; 123:701.
  8. Novak N, Mete N, Bussmann C, et al. Early suppression of basophil activation during allergen-specific immunotherapy by histamine receptor 2. J Allergy Clin Immunol 2012; 130:1153.
  9. Van Metre TE Jr, Adkinson NF Jr, Kagey-Sobotka A, et al. Immunotherapy decreases skin sensitivity to ragweed extract: demonstration by midpoint skin test titration. J Allergy Clin Immunol 1990; 86:587.
  10. Larenas-Linnemann DE, Pietropaolo-Cienfuegos DR, Calderón MA. Evidence of effect of subcutaneous immunotherapy in children: complete and updated review from 2006 onward. Ann Allergy Asthma Immunol 2011; 107:407.
  11. Lichtenstein LM, Ishizaka K, Norman PS, et al. IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. J Clin Invest 1973; 52:472.
  12. Gleich GJ, Zimmermann EM, Henderson LL, Yunginger JW. Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study. J Allergy Clin Immunol 1982; 70:261.
  13. Creticos PS, Van Metre TE, Mardiney MR, et al. Dose response of IgE and IgG antibodies during ragweed immunotherapy. J Allergy Clin Immunol 1984; 73:94.
  14. Radbruch A, Muehlinghaus G, Luger EO, et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 2006; 6:741.
  15. Jutel M, Agache I, Bonini S, et al. International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics. J Allergy Clin Immunol 2016; 137:358.
  16. Peng ZK, Naclerio RM, Norman PS, Adkinson NF Jr. Quantitative IgE- and IgG-subclass responses during and after long-term ragweed immunotherapy. J Allergy Clin Immunol 1992; 89:519.
  17. Aalberse RC, van der Gaag R, van Leeuwen J. Serologic aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4-restricted response. J Immunol 1983; 130:722.
  18. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009; 39:469.
  19. van de Veen W, Stanic B, Yaman G, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol 2013; 131:1204.
  20. van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 2007; 317:1554.
  21. Wachholz PA, Soni NK, Till SJ, Durham SR. Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. J Allergy Clin Immunol 2003; 112:915.
  22. Ozdemir C, Kucuksezer UC, Akdis M, Akdis CA. Mechanisms of Aeroallergen Immunotherapy: Subcutaneous Immunotherapy and Sublingual Immunotherapy. Immunol Allergy Clin North Am 2016; 36:71.
  23. Michils A, Baldassarre S, Ledent C, et al. Early effect of ultrarush venom immunotherapy on the IgG antibody response. Allergy 2000; 55:455.
  24. Michils A, Mairesse M, Ledent C, et al. Modified antigenic reactivity of anti-phospholipase A2 IgG antibodies in patients allergic to bee venom: conversion with immunotherapy and relation to subclass expression. J Allergy Clin Immunol 1998; 102:118.
  25. Batard T, Basuyaux B, Lambin P, et al. Isotypic analysis of grass pollen-specific immunoglobulins in human plasma. 1. Specialization of certain classes and subclasses in the immune response. Int Arch Allergy Immunol 1993; 100:68.
  26. Platts-Mills TA, von Maur RK, Ishizaka K, et al. IgA and IgG anti-ragweed antibodies in nasal secretions. Quantitative measurements of antibodies and correlation with inhibition of histamine release. J Clin Invest 1976; 57:1041.
  27. Meiler F, Klunker S, Zimmermann M, et al. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy 2008; 63:1455.
  28. Stanic B, van de Veen W, Wirz OF, et al. IL-10-overexpressing B cells regulate innate and adaptive immune responses. J Allergy Clin Immunol 2015; 135:771.
  29. Bellinghausen I, Metz G, Enk AH, et al. Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects. Eur J Immunol 1997; 27:1131.
  30. Blaser K, Akdis CA. Interleukin-10, T regulatory cells and specific allergy treatment. Clin Exp Allergy 2004; 34:328.
  31. Francis JN, Till SJ, Durham SR. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol 2003; 111:1255.
  32. Jutel M, Akdis M, Budak F, et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 2003; 33:1205.
  33. Savolainen J, Laaksonen K, Rantio-Lehtimäki A, Terho EO. Increased expression of allergen-induced in vitro interleukin-10 and interleukin-18 mRNA in peripheral blood mononuclear cells of allergic rhinitis patients after specific immunotherapy. Clin Exp Allergy 2004; 34:413.
  34. Akdis M, Verhagen J, Taylor A, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 2004; 199:1567.
  35. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003; 3:253.
  36. Orihara K, Narita M, Tobe T, et al. Circulating Foxp3+CD4+ cell numbers in atopic patients and healthy control subjects. J Allergy Clin Immunol 2007; 120:960.
  37. Varney VA, Hamid QA, Gaga M, et al. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest 1993; 92:644.
  38. Ohashi Y, Nakai Y, Okamoto H, et al. Serum level of interleukin-4 in patients with perennial allergic rhinitis during allergen-specific immunotherapy. Scand J Immunol 1996; 43:680.
  39. Majori M, Caminati A, Corradi M, et al. T-cell cytokine pattern at three time points during specific immunotherapy for mite-sensitive asthma. Clin Exp Allergy 2000; 30:341.
  40. Hamid QA, Schotman E, Jacobson MR, et al. Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J Allergy Clin Immunol 1997; 99:254.
  41. Wambre E, DeLong JH, James EA, et al. Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J Allergy Clin Immunol 2012; 129:544.
  42. Till SJ, Durham SR. Immunological responses to allergen immunotherapy. Clin Allergy Immunol 2004; 18:85.
  43. Till SJ, Francis JN, Nouri-Aria K, Durham SR. Mechanisms of immunotherapy. J Allergy Clin Immunol 2004; 113:1025.
  44. Durham SR, Ying S, Varney VA, et al. Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-gamma. J Allergy Clin Immunol 1996; 97:1356.
  45. Evans R, Pence H, Kaplan H, Rocklin RE. The effect of immunotherapy on humoral and cellular responses in ragweed hayfever. J Clin Invest 1976; 57:1378.
  46. Tulic MK, Fiset PO, Christodoulopoulos P, et al. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol 2004; 113:235.
  47. Montaldo E, Vacca P, Vitale C, et al. Human innate lymphoid cells. Immunol Lett 2016.
  48. Bartemes KR, Kephart GM, Fox SJ, Kita H. Enhanced innate type 2 immune response in peripheral blood from patients with asthma. J Allergy Clin Immunol 2014; 134:671.
  49. Morita H, Arae K, Unno H, et al. An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers. Immunity 2015; 43:175.
  50. Lao-Araya M, Steveling E, Scadding GW, et al. Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy. J Allergy Clin Immunol 2014; 134:1193.
  51. Wilson DR, Irani AM, Walker SM, et al. Grass pollen immunotherapy inhibits seasonal increases in basophils and eosinophils in the nasal epithelium. Clin Exp Allergy 2001; 31:1705.
  52. Monteseirín J, Bonilla I, Camacho J, et al. Elevated secretion of myeloperoxidase by neutrophils from asthmatic patients: the effect of immunotherapy. J Allergy Clin Immunol 2001; 107:623.
  53. Wilson DR, Nouri-Aria KT, Walker SM, et al. Grass pollen immunotherapy: symptomatic improvement correlates with reductions in eosinophils and IL-5 mRNA expression in the nasal mucosa during the pollen season. J Allergy Clin Immunol 2001; 107:971.
  54. Furin MJ, Norman PS, Creticos PS, et al. Immunotherapy decreases antigen-induced eosinophil cell migration into the nasal cavity. J Allergy Clin Immunol 1991; 88:27.
  55. Durham SR, Varney VA, Gaga M, et al. Grass pollen immunotherapy decreases the number of mast cells in the skin. Clin Exp Allergy 1999; 29:1490.
  56. Håkansson L, Heinrich C, Rak S, Venge P. Priming of eosinophil adhesion in patients with birch pollen allergy during pollen season: effect of immunotherapy. J Allergy Clin Immunol 1997; 99:551.
  57. Eberlein-König B, Ullmann S, Thomas P, Przybilla B. Tryptase and histamine release due to a sting challenge in bee venom allergic patients treated successfully or unsuccessfully with hyposensitization. Clin Exp Allergy 1995; 25:704.
  58. Jutel M, Müller UR, Fricker M, et al. Influence of bee venom immunotherapy on degranulation and leukotriene generation in human blood basophils. Clin Exp Allergy 1996; 26:1112.
  59. Plewako H, Wosińska K, Arvidsson M, et al. Basophil interleukin 4 and interleukin 13 production is suppressed during the early phase of rush immunotherapy. Int Arch Allergy Immunol 2006; 141:346.
  60. Shamji MH, Layhadi JA, Scadding GW, et al. Basophil expression of diamine oxidase: a novel biomarker of allergen immunotherapy response. J Allergy Clin Immunol 2015; 135:913.