Allergy Asthma Immunol Res.  2011 Jan;3(1):11-20. 10.4168/aair.2011.3.1.11.

Update in the Mechanisms of Allergen-Specific Immunotheraphy

• Akkoc T
• Akdis M
• Akdis CA

• KMID: 2260372
• DOI: http://doi.org/10.4168/aair.2011.3.1.11

Abstract

Allergic diseases represent a complex innate and adoptive immune response to natural environmental allergens with Th2-type T cells and allergen-specific IgE predominance. Allergen-specific immunotherapy is the most effective therapeutic approach for disregulated immune response towards allergens by enhancing immune tolerance mechanisms. The main aim of immunotherapy is the generation of allergen nonresponsive or tolerant T cells in sensitized patients and downregulation of predominant T cell- and IgE-mediated immune responses. During allergen-specific immunotherapy, T regulatory cells are generated, which secrete IL-10 and induce allergen-specific B cells for the production of IgG4 antibodies. These mechanisms induce tolerance to antigens that reduces allergic symptoms. Although current knowledge highlights the role of T regulatory cell-mediated immunetolerance, definite mechanisms that lead to a successful clinical outcomes of allergen-specific immunotherapy still remains an open area of research.

Keyword

Allergy; T regulatory cells; allergen-specific immunotheraphy; dendiritic cells

MeSH Terms

Allergens
Antibodies
B-Lymphocytes
Down-Regulation
Humans
Hypersensitivity
Immune Tolerance
Immunoglobulin E
Immunoglobulin G
Immunotherapy
Interleukin-10
T-Lymphocytes
Allergens
Antibodies
Immunoglobulin E
Immunoglobulin G
Interleukin-10

Figure

• 

  Figure Mechanisms of allergen-specific immunotherapy. Both subcutaneous and sublingual SITs first affect the regional antigen-presenting cell, namely the local dendritic cell subset in the place of administration and draining lymph nodes. Although in vivo mechanisms are not clearly known, these dendritic cells induce Treg (CD4+CD25+FoxP3+) cells and Tr1 cells (IL-10+). Treg cells and regulatory cytokines (such as interleukin-10 (IL-10) and transforming growth factor-β, TGFβ) may contribute to the control of allergen-induced immune responses in several different ways. TReg cells utilize multiple suppressor factors to regulate the immune response. IL-10 and TGF-β suppress IgE production and IL-10 induces inflammatory immunoglobulin isotype, IgG4. These two cytokines directly suppress allergic inflammation induced by effector cells such as mast cells, basophils and eosinophils. TReg cells influence the generation of dendritic cells and promote the development of IL-10-producing dendritic cells. In addition, TReg cells inhibit Th2 cells, which can no longer provide cytokines such as IL-3, IL-4, IL-5, and IL-9. These cytokines are required for the differentiation, survival and activity of mast cells, basophils, eosinophils and mucus producing cells, as well as for the tissue homing of Th2 cells. SIT, specific immunotherapy; SLIT, sublingual immunotheraphy; SCIT, subcutaneous immunotheraphy; Treg, T regulatory cells.

Reference

1. Akdis CA. Allergy and hypersensitivity: mechanisms of allergic disease. Curr Opin Immunol. 2006. 18:718–726.

2. Palomares O, Yaman G, Azkur AK, Akkoc T, Akdis M, Akdis CA. Role of Treg in immune regulation of allergic diseases. Eur J Immunol. 2010. 40:1232–1240.

3. Akdis M, Akdis CA. Therapeutic manipulation of immune tolerance in allergic disease. Nat Rev Drug Discov. 2009. 8:645–660.

4. Simons FE. Anaphylaxis. J Allergy Clin Immunol. 2010. 125:S161–S181.

5. Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol. 2008. 9:1215–1223.

6. Basinski TM, Holzmann D, Eiwegger T, Zimmermann M, Klunker S, Meyer N, Schmid-Grendelmeier P, Jutel M, Akdis CA. Dual nature of T cell-epithelium interaction in chronic rhinosinusitis. J Allergy Clin Immunol. 2009. 124:74–80.e8.

7. Trautmann A, Akdis M, Kleemann D, Altznauer F, Simon HU, Graeve T, Noll M, Bröcker EB, Blaser K, Akdis CA. T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest. 2000. 106:25–35.

8. Sallusto F, Lanzavecchia A. Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Eur J Immunol. 2009. 39:2076–2082.

9. Schmidt-Weber CB, Akdis M, Akdis CA. TH17 cells in the big picture of immunology. J Allergy Clin Immunol. 2007. 120:247–254.

10. Burgler S, Ouaked N, Bassin C, Basinski TM, Mantel PY, Siegmund K, Meyer N, Akdis CA, Schmidt-Weber CB. Differentiation and functional analysis of human T(H)17 cells. J Allergy Clin Immunol. 2009. 123:588–595.e7.

11. Truyen E, Coteur L, Dilissen E, Overbergh L, Dupont LJ, Ceuppens JL, Bullens DM. Evaluation of airway inflammation by quantitative Th1/Th2 cytokine mRNA measurement in sputum of asthma patients. Thorax. 2006. 61:202–208.

12. Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F, Quesniaux V, Fossiez F, Ryffel B, Schnyder B. Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med. 2006. 203:2715–2725.

13. Burgler S, Mantel PY, Bassin C, Ouaked N, Akdis CA, Schmidt-Weber CB. RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter. J Immunol. 2010. 184:6161–6169.

14. Hellings PW, Kasran A, Liu Z, Vandekerckhove P, Wuyts A, Overbergh L, Mathieu C, Ceuppens JL. Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma. Am J Respir Cell Mol Biol. 2003. 28:42–50.

15. Ciprandi G, Filaci G, Battaglia F, Fenoglio D. Peripheral Th-17 cells in allergic rhinitis: new evidence. Int Immunopharmacol. 2010. 10:226–229.

16. Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol Int. 2008. 57:121–134.

17. Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, Cianfarani F, Odorisio T, Traidl-Hoffmann C, Behrendt H, Durham SR, Schmidt-Weber CB, Cavani A. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009. 119:3573–3585.

18. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburg MM, Mason CA, Iwakura Y, Kolls JK. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008. 14:275–281.

19. Andoh A, Zhang Z, Inatomi O, Fujino S, Deguchi Y, Araki Y, Tsujikawa T, Kitoh K, Kim-Mitsuyama S, Takayanagi A, Shimizu N, Fujiyama Y. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005. 129:969–984.

20. Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol. 2004. 5:1219–1226.

21. Lande R, Gilliet M. Plasmacytoid dendritic cells: key players in the initiation and regulation of immune responses. Ann N Y Acad Sci. 2010. 1183:89–103.

22. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol. 2002. 23:445–449.

23. Fallarino F, Asselin-Paturel C, Vacca C, Bianchi R, Gizzi S, Fioretti MC, Trinchieri G, Grohmann U, Puccetti P. Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement. J Immunol. 2004. 173:3748–3754.

24. Allam JP, Stojanovski G, Friedrichs N, Peng W, Bieber T, Wenzel J, Novak N. Distribution of Langerhans cells and mast cells within the human oral mucosa: new application sites of allergens in sublingual immunotherapy? Allergy. 2008. 63:720–727.

25. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008. 133:775–787.

26. Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol. 2005. 116:949–959. quiz 60.

27. Akdis M, Blaser K, Akdis CA. T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J Allergy Clin Immunol. 2005. 116:961–968. quiz 9.

28. Akdis CA, Akdis M, Blesken T, Wymann D, Alkan SS, Müller U, Blaser K. Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro. J Clin Invest. 1996. 98:1676–1683.

29. Akdis CA, Blesken T, Akdis M, Wüthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest. 1998. 102:98–106.

30. Francis JN, Till SJ, Durham SR. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol. 2003. 111:1255–1261.

31. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA. 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. 33:1205–1214.

32. Klunker S, Chong MM, Mantel PY, Palomares O, Bassin C, Ziegler M, Rückert B, Meiler F, Akdis M, Littman DR, Akdis CA. Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells. J Exp Med. 2009. 206:2701–2715.

33. Verhagen J, Akdis M, Traidl-Hoffmann C, Schmid-Grendelmeier P, Hijnen D, Knol EF, Behrendt H, Blaser K, Akdis CA. Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol. 2006. 117:176–183.

34. Zhou J, Appleton SE, Stadnyk A, Lee TD, Nashan BA. CD8+ gammadelta T regulatory cells mediate kidney allograft prolongation after oral exposure to alloantigen. Transpl Int. 2008. 21:679–687.

35. Ke Y, Kapp JA. Oral antigen inhibits priming of CD8+ CTL, CD4+ T cells, and antibody responses while activating CD8+ suppressor T cells. J Immunol. 1996. 156:916–921.

36. Chen W, Zhou D, Torrealba JR, Waddell TK, Grant D, Zhang L. Donor lymphocyte infusion induces long-term donor-specific cardiac xenograft survival through activation of recipient double-negative regulatory T cells. J Immunol. 2005. 175:3409–3416.

37. Deniz G, Erten G, Kücüksezer UC, Kocacik D, Karagiannidis C, Aktas E, Akdis CA, Akdis M. Regulatory NK cells suppress antigen-specific T cell responses. J Immunol. 2008. 180:850–857.

38. Akdis M. Healthy immune response to allergens: T regulatory cells and more. Curr Opin Immunol. 2006. 18:738–744.

39. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, Kegel C, Disch R, Schmidt-Weber CB, Blaser K, Akdis CA. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med. 2004. 199:1567–1575.

40. Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med. 2008. 205:2887–2898.

41. Carballido JM, Carballido-Perrig N, Kägi MK, Meloen RH, Wüthrich B, Heusser CH, Blaser K. T cell epitope specificity in human allergic and nonallergic subjects to bee venom phospholipase A2. J Immunol. 1993. 150:3582–3591.

42. Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet. 2001. 357:752–756.

43. Frew AJ. Allergen immunotherapy. J Allergy Clin Immunol. 2010. 125:S306–S313.

44. Hendrikx TK, Velthuis JH, Klepper M, van Gurp E, Geel A, Schoordijk W, Baan CC, Weimar W. Monotherapy rapamycin allows an increase of CD4 CD25 FoxP3 T cells in renal recipients. Transpl Int. 2009. 22:884–891.

45. Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W, Steinfeld S, Tindall E, Becker JC, Li T, Nuamah IF, Aranda R, Moreland LW. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005. 52:2263–2271.

46. Utset TO, Auger JA, Peace D, Zivin RA, Xu D, Jolliffe L, Alegre ML, Bluestone JA, Clark MR. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J Rheumatol. 2002. 29:1907–1913.

47. Isaacs JD, Greer S, Sharma S, Symmons D, Smith M, Johnston J, Waldmann H, Hale G, Hazleman BL. Morbidity and mortality in rheumatoid arthritis patients with prolonged and profound therapy-induced lymphopenia. Arthritis Rheum. 2001. 44:1998–2008.

48. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med. 2004. 200:277–285.

49. Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. 2005. 116:608–613.

50. Kussebi F, Karamloo F, Rhyner C, Schmid-Grendelmeier P, Salagianni M, Mannhart C, Akdis M, Soldatova L, Markovic-Housley Z, Von Beust BR, Kundig T, Kemeny DM, Blaser K, Crameri R, Akdis CA. A major allergen gene-fusion protein for potential usage in allergen-specific immunotherapy. J Allergy Clin Immunol. 2005. 115:323–329.

51. Karamloo F, Schmid-Grendelmeier P, Kussebi F, Akdis M, Salagianni M, von Beust BR, Reimers A, Zumkehr J, Soldatova L, Housley-Markovic Z, Müller U, Kündig T, Kemeny DM, Spangfort MD, Blaser K, Akdis CA. Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes. Eur J Immunol. 2005. 35:3268–3276.

52. Niederberger V, Horak F, Vrtala S, Spitzauer S, Krauth MT, Valent P, Reisinger J, Pelzmann M, Hayek B, Kronqvist M, Gafvelin G, Gronlund H, Purohit A, Suck R, Fiebig H, Cromwell O, Pauli G, van Hage-Hamsten M, Valenta R. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci U S A. 2004. 101:Suppl 2. 14677–14682.

53. Larché M. Immunoregulation by targeting T cells in the treatment of allergy and asthma. Curr Opin Immunol. 2006. 18:745–750.

54. Alexander C, Tarzi M, Larché M, Kay AB. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects. Allergy. 2005. 60:1269–1274.

55. Norman PS, Ohman JL Jr, Long AA, Creticos PS, Gefter MA, Shaked Z, Wood RA, Eggleston PA, Hafner KB, Rao P, Lichtenstein LM, Jones NH, Nicodemus CF. Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med. 1996. 154:1623–1628.

56. Müller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, Blaser K. Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J Allergy Clin Immunol. 1998. 101:747–754.

57. Marcotte GV, Braun CM, Norman PS, Nicodemus CF, Kagey-Sobotka A, Lichtenstein LM, Essayan DM. Effects of peptide therapy on ex vivo T-cell responses. J Allergy Clin Immunol. 1998. 101:506–513.

58. von Garnier C, Astori M, Kettner A, Dufour N, Heusser C, Corradin G, Spertini F. Allergen-derived long peptide immunotherapy downregulates specific IgE response and protects from anaphylaxis. Eur J Immunol. 2000. 30:1638–1645.

59. Haselden BM, Kay AB, Larché M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med. 1999. 189:1885–1894.

60. Oldfield WL, 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.

61. Akdis CA, Blaser K. Bypassing IgE and targeting T cells for specific immunotherapy of allergy. Trends Immunol. 2001. 22:175–178.

62. Kahlert H, Suck R, Weber B, Nandy A, Wald M, Keller W, Cromwell O, Fiebig H. Characterization of a hypoallergenic recombinant Bet v 1 variant as a candidate for allergen-specific immunotherapy. Int Arch Allergy Immunol. 2008. 145:193–206.

63. Pree I, Reisinger J, Focke M, Vrtala S, Pauli G, van Hage M, Cromwell O, Gadermaier E, Egger C, Reider N, Horak F, Valenta R, Niederberger V. Analysis of epitope-specific immune responses induced by vaccination with structurally folded and unfolded recombinant Bet v 1 allergen derivatives in man. J Immunol. 2007. 179:5309–5316.

64. Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, Li H, Coffman R, Seyfert V, Eiden JJ, Broide D. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006. 355:1445–1455.

65. Patel P, Salapatek AM. Pollinex Quattro: a novel and well-tolerated, ultra short-course allergy vaccine. Expert Rev Vaccines. 2006. 5:617–629.

66. Puggioni F, Durham SR, Francis JN. Monophosphoryl lipid A (MPL) promotes allergen-induced immune deviation in favour of Th1 responses. Allergy. 2005. 60:678–684.

67. Assessment of the contribution of monophosphoryl lipid A (MPL) to a grass pollen allergy vaccine [Internet]. U.S. National Institute of Health. updated 2010 Jun 16. Available from: http://clinicaltrials.gov/ct2/show/NCT00133146.

68. Kundig TM, Senti G, Schnetzler G, Wolf C, Prinz Vavricka BM, Fulurija A, Hennecke F, Sladko K, Jennings GT, Bachmann MF. Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. J Allergy Clin Immunol. 2006. 117:1470–1476.

69. Casale TB, Busse WW, Kline JN, Ballas ZK, Moss MH, Townley RG, Mokhtarani M, Seyfert-Margolis V, Asare A, Bateman K, Deniz Y. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2006. 117:134–140.

70. Johansen P, Häffner AC, Koch F, Zepter K, Erdmann I, Maloy K, Simard JJ, Storni T, Senti G, Bot A, Wüthrich B, Kündig TM. Direct intralymphatic injection of peptide vaccines enhances immunogenicity. Eur J Immunol. 2005. 35:568–574.

71. Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, Mc-Cormack SJ, Simard JJ, Wüthrich B, Crameri R, Graf N, Johansen P, Kündig TM. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008. 105:17908–17912.

72. Zhu D, Kepley CL, Zhang M, Zhang K, Saxon A. A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. Nat Med. 2002. 8:518–521.

73. Zhu D, Kepley CL, Zhang K, Terada T, Yamada T, Saxon A. A chimeric human-cat fusion protein blocks cat-induced allergy. Nat Med. 2005. 11:446–449.

74. Rhyner C, Kündig T, Akdis CA, Crameri R. Targeting the MHC II presentation pathway in allergy vaccine development. Biochem Soc Trans. 2007. 35:833–834.

75. Evaluation of safety, tolerability, immunogenicity and efficacy of a novel method in specific immunotherapy in cat allergic patients: a placebo controlled trial (IVN-CAT-001B) [Internet]. U.S. National Institute of Health. updated 2010 Feb 10. Available from: http://clinicaltrials.gov/ct2/show/study/NCT00718679.

76. O'Connor RA, Anderton SM. Multi-faceted control of autoaggression: Foxp3+ regulatory T cells in murine models of organ-specific autoimmune disease. Cell Immunol. 2008. 251:8–18.

77. Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007. 7:585–598.

78. Peek EJ, Richards DF, Faith A, Lavender P, Lee TH, Corrigan CJ, Hawrylowicz CM. Interleukin-10-secreting "regulatory" T cells induced by glucocorticoids and beta2-agonists. Am J Respir Cell Mol Biol. 2005. 33:105–111.

79. Karagiannidis C, Akdis M, Holopainen P, Woolley NJ, Hense G, Ruckert B, Mantel PY, Menz G, Akdis CA, Blaser K, Schmidt-Weber CB. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol. 2004. 114:1425–1433.

80. Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2007. 119:780–791.

81. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy. 2005. 60:4–12.

82. Gidaro GB, Marcucci F, Sensi L, Incorvaia C, Frati F, Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies. Clin Exp Allergy. 2005. 35:565–571.

83. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007. CD001936.

84. Calderón MA, Penagos M, Durham SR. Sublingual immunotherapy for allergic Rhinoconjunctivitis, allergic asthma, and prevention of allergic diseases. Clin Allergy Immunol. 2008. 21:359–375.

85. Novak N, Haberstok J, Bieber T, Allam JP. The immune privilege of the oral mucosa. Trends Mol Med. 2008. 14:191–198.

86. Marcucci F, Incorvaia C, Sensi L, Di Cara G, Cadario G, Cavaliere A, Moingeon P, Puccinelli P, Di Gioacchino M, Frati F. Lack of inflammatory cells in the oral mucosa of subjects undergoing sublingual immunotherapy. Int J Immunopathol Pharmacol. 2008. 21:609–613.

87. Allam JP, Novak N, Fuchs C, Asen S, Bergé S, Appel T, Geiger E, Kochan JP, Bieber T. Characterization of dendritic cells from human oral mucosa: a new Langerhans' cell type with high constitutive FcepsilonRI expression. J Allergy Clin Immunol. 2003. 112:141–148.

88. Allam JP, Peng WM, Appel T, Wenghoefer M, Niederhagen B, Bieber T, Bergé S, Novak N. Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells. J Allergy Clin Immunol. 2008. 121:368–374.e1.

89. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J Allergy Clin Immunol. 2010. 125:569–574.e7.

90. Werfel T, Breuer K, Ruéff F, Przybilla B, Worm M, Grewe M, Ruzicka T, Brehler R, Wolf H, Schnitker J, Kapp A. Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose-response study. Allergy. 2006. 61:202–205.

91. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Høst A, Koivikko A, Norberg LA, Valovirta E, Wahn U, Möller C. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007. 62:943–948.

92. Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, Carr VA, Robinson DS. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet. 2004. 363:608–615.

93. Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997. 389:737–742.

94. Akdis CA, Kussebi F, Pulendran B, Akdis M, Lauener RP, Schmidt-Weber CB, Klunker S, Isitmangil G, Hansjee N, Wynn TA, Dillon S, Erb P, Baschang G, Blaser K, Alkan SS. Inhibition of T helper 2-type responses, IgE production and eosinophilia by synthetic lipopeptides. Eur J Immunol. 2003. 33:2717–2726.

95. Izcue A, Coombes JL, Powrie F. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol. 2009. 27:313–338.

96. Izcue A, Hue S, Buonocore S, Arancibia-Cárcamo CV, Ahern PP, Iwakura Y, Maloy KJ, Powrie F. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity. 2008. 28:559–570.

97. Steinbrink K, Wölfl M, Jonuleit H, Knop J, Enk AH. Induction of tolerance by IL-10-treated dendritic cells. J Immunol. 1997. 159:4772–4780.

98. Wu K, Bi Y, Sun K, Xia J, Wang Y, Wang C. Suppression of allergic inflammation by allergen-DNA-modified dendritic cells depends on the induction of Foxp3+ Regulatory T cells. Scand J Immunol. 2008. 67:140–151.

99. Bellinghausen I, Brand U, Steinbrink K, Enk AH, Knop J, Saloga J. Inhibition of human allergic T-cell responses by IL-10-treated dendritic cells: differences from hydrocortisone-treated dendritic cells. J Allergy Clin Immunol. 2001. 108:242–249.

100. Kearley J, Barker JE, Robinson DS, Lloyd CM. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med. 2005. 202:1539–1547.

101. Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy. 2008. 63:1455–1463.

102. Gri G, Piconese S, Frossi B, Manfroi V, Merluzzi S, Tripodo C, Viola A, Odom S, Rivera J, Colombo MP, Pucillo CE. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity. 2008. 29:771–781.

103. Kearley J, Robinson DS, Lloyd CM. CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. J Allergy Clin Immunol. 2008. 122:617–624.e6.

104. Burchell JT, Wikstrom ME, Stumbles PA, Sly PD, Turner DJ. Attenuation of allergen-induced airway hyperresponsiveness is mediated by airway regulatory T cells. Am J Physiol Lung Cell Mol Physiol. 2009. 296:L307–L319.

105. Radulovic S, Jacobson MR, Durham SR, Nouri-Aria KT. Grass pollen immunotherapy induces Foxp3-expressing CD4+CD25+ cells in the nasal mucosa. J Allergy Clin Immunol. 2008. 121:1467–1472.e1.

106. James LK, Durham SR. Update on mechanisms of allergen injection immunotherapy. Clin Exp Allergy. 2008. 38:1074–1088.

107. Pilette C, Nouri-Aria KT, Jacobson MR, Wilcock LK, Detry B, Walker SM, Francis JN, Durham SR. Grass pollen immunotherapy induces an allergen-specific IgA2 antibody response associated with mucosal TGF-beta expression. J Immunol. 2007. 178:4658–4666.

108. van Neerven RJ, Arvidsson M, Ipsen H, Sparholt SH, Rak S, Würtzen PA. A double-blind, placebo-controlled birch allergy vaccination study: inhibition of CD23-mediated serum-immunoglobulin E-facilitated allergen presentation. Clin Exp Allergy. 2004. 34:420–428.

109. Akdis CA, Blaser K. IL-10-induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. FASEB J. 1999. 13:603–609.

110. Varney VA, Hamid QA, Gaga M, Ying S, Jacobson M, Frew AJ, Kay AB, Durham SR. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest. 1993. 92:644–651.

111. Jutel M, Pichler WJ, Skrbic D, Urwyler A, Dahinden C, Müller UR. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. J Immunol. 1995. 154:4187–4194.

112. Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, Kay AB, Hamid QA. 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. 97:1356–1365.

113. 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. 2010. 40:598–606.

114. Stavnezer J, Guikema JE, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008. 26:261–292.

115. Müller U, Helbling A, Bischof M. Predictive value of venom-specific IgE, IgG and IgG subclass antibodies in patients on immunotherapy with honey bee venom. Allergy. 1989. 44:412–418.