Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Therapeutic manipulation of immune tolerance in allergic disease

Nature Reviews Drug Discovery volume 8, pages 645–660 (2009)Cite this article

Key Points

  • Immune tolerance — the adaptation of the immune system to external antigens or allergens — might be therapeutically manipulated to restore normal immunity in conditions such as allergy, asthma and autoimmune diseases.

  • The physiopathology of immune-tolerance-related diseases is complex and is influenced by several factors.

  • T regulatory (TReg) cells have become a prime target for strategies aimed at inducing immune tolerance. Their pivotal role in maintaining immune tolerance was demonstrated in animal models — including allergy, asthmatic lung inflammation, autoimmune diseases and allograft rejection — by restoring immune tolerance to allergens, self antigens or alloantigens.

  • In allergen-specific immunotherapy (SIT) peripheral T-cell tolerance is initiated by the increased autocrine action of allergen-specific TReg cells.

  • TReg cells directly or indirectly contribute to the control of allergen-specific immune responses at the level of antigen presentation, T-cell suppression, antibody regulation, suppression of mast cells, basophils and eosinophils, and interaction with resident tissue cells and tissue remodelling in the inflamed lung, nose and skin.

  • Allergen-SIT in humans faces several problems related to the content of the vaccine, type of the adjuvant, route of application, long duration of treatment, side effects and limited efficacy. For this reason intensive research has been carried out to improve efficacy and safety of allergen-SIT during the past several years and many promising studies have been completed.

  • There is a substantial focus on the development of immunomodulatory drugs for allergy and asthma. Some of these could be combined with allergen-SIT to improve their efficacy and safety.

Abstract

Immune tolerance — the adaptation of the immune system to external antigens or allergens — might be therapeutically manipulated to restore normal immunity in conditions such as allergy, asthma and autoimmune diseases. The field of allergen-specific immunotherapy is experiencing exciting and novel developments for the treatment of allergic and autoimmune diseases, and recent insights into the reciprocal regulation and counter-balance between different T-cell subsets is foreseen to facilitate new strategies for immunointervention. This Review highlights current knowledge of immunomodulatory therapies for the manipulation of immune tolerance and highlights recent approaches to improve allergen-specific immunotherapy for the treatment of allergic diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The four sequential processes characterizing allergic inflammation.
Figure 2: Development of effector T-cell subsets.
Figure 3: Functions of TH1, TH2, TH17, and TReg cells.
Figure 4: TReg cells in allergic immune response.
Figure 5: IgE production and type-1 hypersensitivity reactions.
Figure 6: Potential targets for immunomodulatory drugs that may improve allergen-specific immunotherapy (SIT).

Similar content being viewed by others

References

  1. Akdis, C. A. Mechanisms of allergic disease. Curr. Opin Immunol. 18, 718–726 (2006).

    CAS  PubMed  Google Scholar 

  2. Noon, L. Prophylactic inoculation against hay fever. Lancet i, 1572–1573 (1911).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Larche, M., Akdis, C. A. & Valenta, R. Immunological mechanisms of allergen-specific immunotherapy. Nature. Rev. Immunol. 6, 761–771 (2006).

    CAS  Google Scholar 

  5. Durham, S. R. et al. Long-term clinical efficacy of grass-pollen immunotherapy. N. Engl. J. Med. 341, 468–475 (1999).

    CAS  PubMed  Google Scholar 

  6. Pajno, G. B., Barberio, G., De Luca, F., Morabito, L. & Parmiani, S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin. Exp. Allergy 31, 1392–1397 (2001).

    CAS  PubMed  Google Scholar 

  7. Moller, C. et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J. Allergy Clin. Immunol. 109, 251–256 (2002).

    PubMed  Google Scholar 

  8. Akdis, C. A. et al. 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. 98, 1676–1683 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Akdis, C. A., Blesken, T., Akdis, M., Wuthrich, B. & Blaser, K. Role of interleukin 10 in specific immunotherapy. J. Clin. Invest. 102, 98–106 (1998). This study demonstrated that CD4+ CD25+ and allergen-specific T Reg cells secrete increasing amounts of IL-10 during the first month of bee venom allergen-SIT.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Francis, J. N., Till, S. J. & Durham, S. R. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J. Allergy Clin. Immunol. 111, 1255–1261 (2003).

    CAS  PubMed  Google Scholar 

  11. Ling, E. M. et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–615 (2004).

    CAS  PubMed  Google Scholar 

  12. Jutel, M. 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. 33, 1205–1214 (2003).

    CAS  PubMed  Google Scholar 

  13. Akdis, M. et al. Skin homing (Cutaneous Lymphocyte-Associated Antigen-positive) CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J. Immunol. 163, 466–475 (1999).

    CAS  PubMed  Google Scholar 

  14. Abernathy-Carver, K. J., Sampson, H. A., Picker, L. J. & Leung, D. Y. M. Milk-induced eczema is associated with the expansion of T cells expressing cutaneous lymphocyte antigen. J. Clin. Invest. 95, 913–918 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).

    CAS  PubMed  Google Scholar 

  16. Gould, H. J. & Sutton, B. J. IgE in allergy and asthma today. Nature Rev. Immunol. 8, 205–217 (2008).

    CAS  Google Scholar 

  17. Mei, H. E. et al. Blood-borne human plasma cells in steady-state are derived from mucosal immune responses. Blood (2008).

  18. Burgler, S. et al. Differentiation and functional analysis of human T(H)17 cells. J. Allergy Clin. Immunol. (2009).

  19. Matsushita, S. & Higashi, T. Human Th17 cell clones and natural immune responses. Allergol. Int. 57, 135–140 (2008).

    CAS  PubMed  Google Scholar 

  20. Dardalhon, V. et al. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nature Immunol. 9, 1347–1355 (2008). This study demonstrated that IL-9+ IL-10+ T cells lack suppressive function and constitute a distinct population of helper–effector T cells that promote tissue inflammation.

    CAS  Google Scholar 

  21. Veldhoen, M. et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunol. 9, 1341–1346 (2008).

    CAS  Google Scholar 

  22. Prussin, C. Cytokine flow cytometry: understanding cytokine biology at the single-cell level. J. Clin. Immunol. 17, 195–204 (1997).

    CAS  PubMed  Google Scholar 

  23. Simon, H.-U. & Blaser, K. Inhibition of programmed eosinophil death: A key pathogenic event for eosinophilia. Immunol. Today 16, 53–55 (1995).

    CAS  PubMed  Google Scholar 

  24. Whittaker, L. et al. Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9. Am. J. Respir. Cell. Mol. Biol. 27, 593–602 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  26. Chatila, T. A. Role of regulatory T cells in human diseases. J. Allergy Clin. Immunol. 116, 949–959; quiz 960 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Verhagen, J. et al. Absence of T-regulatory cell expression and function in atopic dermatitis skin. J. Allergy Clin. Immunol. 117, 176–183 (2006).

    CAS  PubMed  Google Scholar 

  29. Deniz, G. et al. Regulatory NK cells suppress antigen-specific T cell responses. J. Immunol. 180, 850–857 (2008).

    CAS  PubMed  Google Scholar 

  30. Zhou, J., Appleton, S. E., Stadnyk, A., Lee, T. D. & Nashan, B. A. CD8(+)gammadelta T regulatory cells mediate kidney allograft prolongation after oral exposure to alloantigen. Transpl. Int. (2008). The authors examined the nature of the immune regulation initiated by oral exposure to alloantigen and demonstrated that the CD8+ T Reg cell that is generated by oral exposure to alloantigen is an IL-10 secreting, γδ TCR+ T cell.

  31. Akdis, M. 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. 199, 1567–1575 (2004). This study demonstrated that IL-10-secreting T R 1 cells expressing multiple suppressor mechanisms, such as IL-10, TGFb, CTLA4 and PD1 consistently represent the dominant subset specific for common environmental allergens in healthy individuals.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Meiler, F. et al. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J. Exp. Med. 205, 2887–2898 (2008). Exposure of non-allergic beekeepers to a high dose of bee venom antigens induces a switch from antigen-specific T H 1 and T H 2 cells toward IL-10 secreting T R 1 cells, which continues as long as antigen exposure persists and returns to initial levels 2 to 3 months after the bee sting.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Carballido, J. M. et al. T cell epitope specificity in human allergic and non-allergic subjects to bee venom phospholipase A2 . J. Immunol. 150, 3582–3591 (1993).

    CAS  PubMed  Google Scholar 

  34. 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 357, 752–756 (2001).

    CAS  PubMed  Google Scholar 

  35. Reefer, A. J. et al. A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events in development of the modified Th2 response to cat allergen. J. Immunol. 172, 2763–2772 (2004).

    CAS  PubMed  Google Scholar 

  36. Steinbrink, K., Wolfl, M., Jonuleit, H., Knop, J. & Enk, A. H. Induction of tolerance by IL-10-treated dendritic cells. J. Immunol. 159, 4772–4780 (1997).

    CAS  PubMed  Google Scholar 

  37. Wu, K. et al. Suppression of allergic inflammation by allergen-DNA-modified dendritic cells depends on the induction of Foxp3+ Regulatory T cells. Scand. J. Immunol. 67, 140–151 (2008).

    CAS  PubMed  Google Scholar 

  38. Bellinghausen, I. et al. Inhibition of human allergic T-cell responses by IL-10-treated dendritic cells: differences from hydrocortisone-treated dendritic cells. J. Allergy Clin. Immunol. 108, 242–249 (2001).

    CAS  PubMed  Google Scholar 

  39. Kearley, J., Barker, J. E., Robinson, D. S. & Lloyd, C. M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J. Exp. Med. 202, 1539–1547 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Meiler, F., Klunker, S., Zimmermann, M., Akdis, C. A. & Akdis, M. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy 63, 1455–1463 (2008).

    CAS  PubMed  Google Scholar 

  41. Gri, G. et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40–OX40L interaction. Immunity 29, 771–781 (2008). This study demonstrated that T Reg cells directly inhibited the FcɛRI-dependent mast cell degranulation through OX40-OX40L interactions.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kearley, J., Robinson, D. S. & Lloyd, C. M. CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. J. Allergy Clin. Immunol. 122, 617–624 e616 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Burchell, J. T., Wikstrom, M. E., Stumbles, P. A., Sly, P. D. & Turner, D. J. Attenuation of allergen-induced airway hyperresponsiveness is mediated by airway regulatory T cells. Am. J. Physiol. Lung Cell Mol. Physiol. 296, 307–319 (2009).

    Google Scholar 

  44. Hendrikx, T. K. et al. Monotherapy rapamycin allows an increase of CD4(+) CD25(bright+) FoxP3(+) T cells in renal recipients. Transpl. Int. 30 Apr 2009 (doi:10.1111/j.142-227.2009.00890.x).

  45. Kremer, J. M. et al. 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. 52, 2263–2271 (2005).

    CAS  PubMed  Google Scholar 

  46. Utset, T. O. et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J. Rheumatol 29, 1907–1913 (2002).

    CAS  PubMed  Google Scholar 

  47. Isaacs, J. D. et al. Morbidity and mortality in rheumatoid arthritis patients with prolonged and profound therapy-induced lymphopenia. Arthritis Rheum. 44, 1998–2008 (2001).

    CAS  PubMed  Google Scholar 

  48. Ehrenstein, M. R. et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J. Exp. Med. 200, 277–285 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. O'Connor, R. A. & Anderton, S. M. Multi-faceted control of autoaggression: Foxp3+ regulatory T cells in murine models of organ-specific autoimmune disease. Cell Immunol. 251, 8–18 (2008).

    CAS  PubMed  Google Scholar 

  50. Roncarolo, M. G. & Battaglia, M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nature Rev. Immunol. 7, 585–598 (2007).

    CAS  Google Scholar 

  51. Morse, M. A. et al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 112, 610–618 (2008). This study demonstrated that a CD25high targeting IL-2 and diphteria toxin fusion protein depleted FoxP3+ T Reg cells, decreased T Reg -cell function and enhanced antigen-specific T-cell responses.

  52. Goforth, R. et al. Immune stimulatory antigen loaded particles combined with depletion of regulatory T-cells induce potent tumor specific immunity in a mouse model of melanoma. Cancer Immunol. Immunother. 58, 517–530 (2009).

    CAS  PubMed  Google Scholar 

  53. Peek, E. J. et al. Interleukin-10-secreting “regulatory” T cells induced by glucocorticoids and beta2-agonists. Am. J. Respir. Cell Mol. Biol. 33, 105–111 (2005).

    CAS  PubMed  Google Scholar 

  54. Karagiannidis, C. et al. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J. Allergy Clin. Immunol. 114, 1425–1433 (2004).

    CAS  PubMed  Google Scholar 

  55. Akdis, M. & Akdis, C. A. Mechanisms of allergen-specific immunotherapy. J. Allergy Clin. Immunol. 119, 780–791 (2007).

    CAS  PubMed  Google Scholar 

  56. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    CAS  PubMed  Google Scholar 

  57. Akdis, C. A. et al. Inhibition of T helper 2-type responses, IgE production and eosinophilia by synthetic lipopeptides. Eur J. Immunol. 33, 2717–2726 (2003).

    CAS  PubMed  Google Scholar 

  58. Izcue, A. et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008). This study demonstrated that IL-23-dependent colitis did not require IL-17 secretion by T cells and IL-23 in the intestine, and could influence not only T h 17 cell activity but also other types of immune responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A. & Weiner, H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).

    CAS  PubMed  Google Scholar 

  60. Fukaura, H. et al. Induction of circulating myelin basic protein and proteolipid protein- specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J. Clin. Invest. 98, 70–77 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Akdis, C. A. & Blaser, K. IL-10 induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. Faseb. J. 13, 603–609 (1999).

    CAS  PubMed  Google Scholar 

  62. Varney, V. A. et al. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J. Clin. Invest. 92, 644–651 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Jutel, M. et al. Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-g secretion in specific allergen stimulated T cell cultures. J. Immunol. 154, 4178–4194 (1995).

    Google Scholar 

  64. Durham, S. R. 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. 97, 1356–1365 (1996).

    CAS  PubMed  Google Scholar 

  65. Nouri-Aria, K. T. et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J. Immunol. 172, 3252–3259 (2004).

    CAS  PubMed  Google Scholar 

  66. Pilette, C. et al. Grass pollen immunotherapy induces an allergen-specific IgA2 antibody response associated with mucosal TGF-beta expression. J. Immunol. 178, 4658–4666 (2007).

    CAS  PubMed  Google Scholar 

  67. Radulovic, S., Jacobson, M. R., Durham, S. R. & Nouri-Aria, K. T. Grass pollen immunotherapy induces Foxp3-expressing CD4+ CD25+ cells in the nasal mucosa. J. Allergy Clin. Immunol. 121, 1467–1472 (2008).

    CAS  PubMed  Google Scholar 

  68. Stavnezer, J., Guikema, J. E. & Schrader, C. E. Mechanism and regulation of class switch recombination. Annu Rev. Immunol. 26, 261–292 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Aalberse, R. C. & Platts-Mills, T. A. How do we avoid developing allergy: modifications of the TH2 response from a B-cell perspective. J. Allergy Clin. Immunol. 113, 983–986 (2004).

    CAS  PubMed  Google Scholar 

  70. Golden, D. B., Meyers, D. A., Kagey-Sobotka, A., Valentine, M. D. & Lichtenstein, L. M. Clinical relevance of the venom-specific immunoglobulin G antibody level during immunotherapy. J. Allergy Clin. Immunol. 69, 489–493 (1982).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  72. van der Giessen, M., Homan, W. L., van Kernbeek, G., Aalberse, R. C. & Dieges, P. H. Subclass typing of IgG antibodies formed by grass pollen-allergic patients during immunotherapy. Int. Arch. Allergy Appl. Immunol. 50, 625–640 (1976).

    CAS  PubMed  Google Scholar 

  73. Jutel, M. et al. Allergen-specific immunotherapy with recombinant grass pollen allergens. J. Allergy Clin. Immunol. 116, 608–613 (2005).

    CAS  PubMed  Google Scholar 

  74. Reisinger, J. et al. Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity. J. Allergy Clin. Immunol. 116, 347–354 (2005).

    CAS  PubMed  Google Scholar 

  75. Kehry, M. R. & Yamashita, L. C. Low-affinity IgE receptor (CD23) function on mouse B cells: role in IgE-dependent antigen focusing. Proc. Natl Acad. Sci. USA 86, 7556–7560 (1989).

    CAS  PubMed  Google Scholar 

  76. van Neerven, R. J. et al. Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. J. Immunol. 163, 2944–2952 (1999).

    CAS  PubMed  Google Scholar 

  77. Wachholz, P. A. & Durham, S. R. Mechanisms of immunotherapy: IgG revisited. Curr. Opin Allergy Clin. Immunol. 4, 313–318 (2004).

    CAS  PubMed  Google Scholar 

  78. Till, S. J., Francis, J. N., Nouri-Aria, K. & Durham, S. R. Mechanisms of immunotherapy. J. Allergy Clin. Immunol. 113, 1025–1034 (2004).

    CAS  PubMed  Google Scholar 

  79. Aalberse, R. C. & Schuurman, J. IgG4 breaking the rules. Immunology 105, 9–19 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. van der Neut Kolfschoten, M. et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317, 1554–1557 (2007).

    Google Scholar 

  81. Jakobsen, C. G., Bodtger, U., Kristensen, P., Poulsen, L. K. & Roggen, E. L. Isolation of high-affinity human IgE and IgG antibodies recognising Bet v 1 and Humicola lanuginosa lipase from combinatorial phage libraries. Mol. Immunol. 41, 941–953 (2004).

    CAS  PubMed  Google Scholar 

  82. Jakobsen, C. G., Bodtger, U., Poulsen, L. K. & Roggen, E. L. Vaccination for birch pollen allergy: comparison of the affinities of specific immunoglobulins E, G1 and G4 measured by surface plasmon resonance. Clin. Exp. Allergy 35, 193–198 (2005).

    CAS  PubMed  Google Scholar 

  83. Klunker, S. et al. Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: Inhibition of IgE-facilitated allergen binding. J. Allergy Clin. Immunol. 120, 688–695 (2007).

    CAS  PubMed  Google Scholar 

  84. Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nature Rev. Immunol. 6, 741–750 (2006).

    CAS  Google Scholar 

  85. Pierkes, M. et al. Decreased release of histamine and sulfidoleukotrienes by human peripheral blood leukocytes after wasp venom immunotherapy is partially due to induction of IL-10 and IFN-gamma production of T cells. J. Allergy Clin. Immunol. 103, 326–332 (1999).

    CAS  PubMed  Google Scholar 

  86. Shim, Y. K., Kim, B. S., Cho, S. H., Min, K. U. & Hong, S. J. Allergen-specific conventional immunotherapy decreases immunoglobulin E-mediated basophil histamine releasability. Clin. Exp. Allergy 33, 52–57 (2003).

    CAS  PubMed  Google Scholar 

  87. Marshall, J. S., Leal-Berumen, I., Nielsen, L., Glibetic, M. & Jordana, M. Interleukin (IL)-10 Inhibits long-term IL-6 production but not preformed mediator release from rat peritoneal mast cells. J. Clin. Invest. 97, 1122–1128 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Schandane, L. et al. B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10. J. Immunol. 152, 4368–4374 (1994).

    Google Scholar 

  89. Palaniyandi, S. S. et al. Inhibition of mast cells by interleukin-10 gene transfer contributes to protection against acute myocarditis in rats. Eur. J. Immunol. 34, 3508–3515 (2004).

    CAS  PubMed  Google Scholar 

  90. Rak, S., Lowhagen, O. & Venge, P. The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. J. Allergy Clin. Immunol. 82, 470–480 (1988).

    CAS  PubMed  Google Scholar 

  91. Hakansson, 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. 99, 551–562 (1997).

    CAS  PubMed  Google Scholar 

  92. Rak, S., Hakanson, L. & Venge, P. Immunotherapy abrogates the generation of eosinophil and neutrophil chemotactic activity during pollen season. J. Allergy Clin. Immunol. 86, 706–713 (1990).

    CAS  PubMed  Google Scholar 

  93. Lewkowicz, P., Lewkowicz, N., Sasiak, A. & Tchorzewski, H. Lipopolysaccharide-activated CD4+CD25+ T regulatory cells inhibit neutrophil function and promote their apoptosis and death. J. Immunol. 177, 7155–7163 (2006).

    CAS  PubMed  Google Scholar 

  94. Ley, K., Smith, E. & Stark, M. A. IL-17A-producing neutrophil-regulatory Tn lymphocytes. Immunol. Res. 34, 229–242 (2006).

    CAS  PubMed  Google Scholar 

  95. Akdis, C. A. Future of allergen-specific immunotherapy: better understanding of the mechanisms, novel treatments, and long-term cure. Immuno. Allergy Clin. North Am. 26, xiii–xxii (2006).

    Google Scholar 

  96. Crameri, R. & Rhyner, C. Novel vaccines and adjuvants for allergen-specific immunotherapy. Curr. Opin Immunol. 18, 761–768 (2006).

    CAS  PubMed  Google Scholar 

  97. Spangfort, M. D. & Larsen, J. N. Standardization of allergen-specific immunotherapy vaccines. Immunol. Allergy Clin. North Am. 26, 191–206, v-vi (2006).

    PubMed  Google Scholar 

  98. Moverare, R., Elfman, L., Vesterinen, E., Metso, T. & Haahtela, T. Development of new IgE specificities to allergenic components in birch pollen extract during specific immunotherapy studied with immunoblotting and Pharmacia CAP System. Allergy 57, 423–430 (2002).

    CAS  PubMed  Google Scholar 

  99. Passalacqua, G. et al. New insights in sublingual immunotherapy. Curr. Allergy Asthma Rep. 6, 407–412 (2006).

    CAS  PubMed  Google Scholar 

  100. Wilson, D. R., Lima, M. T. & Durham, S. R. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 60, 4–12 (2005).

    CAS  PubMed  Google Scholar 

  101. Coyle, A. J. et al. Central role of immunoglobulin-E in the induction of lung eosinophil infiltration and T helper 2 cell cytokine production: inhibition by a non-anaphylactogenic anti-IgE antibody J. Exp. Med. 183, 1303–1308 (1996).

    CAS  PubMed  Google Scholar 

  102. Akdis, C. A. & Blaser, K. Bypassing IgE and targeting T cells for specific immunotherapy of allergy. Trends Immunol. 22, 175–178 (2001).

    CAS  PubMed  Google Scholar 

  103. Kahlert, H. et al. Characterization of a hypoallergenic recombinant Bet v 1 variant as a candidate for allergen-specific immunotherapy. Int. Arch. Allergy Immunol. 145, 193–206 (2008).

    CAS  PubMed  Google Scholar 

  104. Pree, I. et al. Analysis of epitope-specific immune responses induced by vaccination with structurally folded and unfolded recombinant Bet v 1 allergen derivatives in man. J. Immunol. 179, 5309–5316 (2007).

    CAS  PubMed  Google Scholar 

  105. Norman, P. et al. Treatment of cat allergy with T cell reactive peptides. Am. J. Repiratory Critical Care Med. 154, 1623–1628 (1996).

    CAS  Google Scholar 

  106. Müller, U. R. et al. Successful immunotherapy with T cell epitope peptides of bee venom phospholipase A2 induces specific T cell anergy in bee sting allergic patients. J. Allergy Clin. Immunol. 101, 747–754 (1998).

    PubMed  Google Scholar 

  107. Marcotte, G. V. et al. Effects of peptide therapy on ex vivo T cell responses. J. Allergy Clin. Immunol. 101, 506–513 (1998).

    CAS  PubMed  Google Scholar 

  108. von Garnier, C. et al. Allergen-derived long peptide immunotherapy down-regulates specific IgE response and protects from anaphylaxis. Eur. J. Immunol. 30, 1638–1645 (2000).

    CAS  PubMed  Google Scholar 

  109. Haselden, B. M., Kay, A. B. & Larche, M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J. Exp. Med. 189, 1885–1894 (1999). This study demonstrated that short, allergen-derived peptides could directly initiate a major histocompatibility complex-restricted, T-cell-dependent late asthmatic reaction, without the requirement for an early IgE or mast-cell-dependent response, in sensitized subjects with asthma.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Oldfield, W. L., Larche, M. & Kay, A. B. 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 360, 47–53 (2002).

    CAS  PubMed  Google Scholar 

  111. Larche, M. Immunoregulation by targeting T cells in the treatment of allergy and asthma. Curr. Opin Immunol. 18, 745–750 (2006).

    CAS  PubMed  Google Scholar 

  112. Raz, I. et al. Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 358, 1749–1753 (2001).

    CAS  PubMed  Google Scholar 

  113. Prakken, B. J. et al. Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 101, 4228–4233 (2004).

    CAS  PubMed  Google Scholar 

  114. Kussebi, F. et al. A major allergen gene-fusion protein for potential usage in allergen-specific immunotherapy. J. Allergy Clin. Immunol. 115, 323–329 (2005).

    CAS  PubMed  Google Scholar 

  115. Karamloo, F. et al. Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes. Eur. J. Immunol. 35, 3268–3276 (2005).

    CAS  PubMed  Google Scholar 

  116. Niederberger, V. et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc. Natl Acad. Sci. USA 101, Suppl 2, 14677–14682 (2004).

    CAS  PubMed  Google Scholar 

  117. Purohit, A. et al. Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives. Clin. Exp. Allergy 38, 1514–1525 (2008).

    CAS  PubMed  Google Scholar 

  118. Valenta, R. et al. The recombinant allergen-based concept of component-resolved diagnostics and immunotherapy (CRD and CRIT). Clin. Exp. Allergy 29, 896–904 (1999).

    CAS  PubMed  Google Scholar 

  119. Valenta, R., Twaroch, T. & Swoboda, I. Component-resolved diagnosis to optimize allergen-specific immunotherapy in the Mediterranean area. J. Investig. Allergol. Clin. Immunol. 17, Suppl 1, 36–40 (2007).

    PubMed  Google Scholar 

  120. Constantin, C. et al. Micro-arrayed wheat seed and grass pollen allergens for component-resolved diagnosis. Allergy 10 Feb 2009 [epub ahead of print].

  121. Zhu, D., Kepley, C. L., Zhang, M., Zhang, K. & Saxon, A. A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. Nature 8, 518–521 (2002).

    CAS  Google Scholar 

  122. Zhu, D. et al. A chimeric human–cat fusion protein blocks cat-induced allergy. Nature Med. 11, 446–449 (2005). This study demonstrated that a chimeric human-cat fusion protein composed of a truncated human IgG Fcγ1 and the major cat allergen Fel d1 inhibited Fel-d1-driven IgE-mediated histamine release from basophils from subjects that were allergic to cats and sensitized human cord blood-derived mast cells.

    CAS  PubMed  Google Scholar 

  123. Rhyner, C., Kundig, T., Akdis, C. A. & Crameri, R. Targeting the MHC II presentation pathway in allergy vaccine development. Biochem. Soc. Trans. 35, 833–834 (2007).

    CAS  PubMed  Google Scholar 

  124. Wang, R. F., Miyahara, Y. & Wang, H. Y. Toll-like receptors and immune regulation: implications for cancer therapy. Oncogene 27, 181–189 (2008).

    PubMed  Google Scholar 

  125. Alegre, M. L. et al. The multiple facets of toll-like receptors in transplantation biology. Transplantation 86, 1–9 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Lombardi, V. et al. Toll-like receptor 2 agonist Pam3CSK4 enhances the induction of antigen-specific tolerance via the sublingual route. Clin. Exp. Allergy 38, 1819–1829 (2008).

    CAS  PubMed  Google Scholar 

  127. Johnson, A. G., Tomai, M., Solem, L., Beck, L. & Ribi, E. Characterization of a nontoxic monophosphoryl lipid A. Rev. Infect. Dis. 9, Suppl 5, 512–516 (1987).

    Google Scholar 

  128. Tapping, R. I., Akashi, S., Miyake, K., Godowski, P. J. & Tobias, P. S. Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. J. Immunol. 165, 5780–5787 (2000).

    CAS  PubMed  Google Scholar 

  129. Baldridge, J. R. et al. Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opin Biol. Ther. 4, 1129–1138 (2004).

    CAS  PubMed  Google Scholar 

  130. Kawai, T. & Akira, S. TLR signaling. Semin. Immunol. 19, 24–32 (2007).

    CAS  PubMed  Google Scholar 

  131. Casale, T. B., Kessler, J. & Romero, F. A. Safety of the intranasal toll-like receptor 4 agonist CRX-675 in allergic rhinitis. Ann. Allergy Asthma Immunol. 97, 454–456 (2006).

    CAS  PubMed  Google Scholar 

  132. Patel, P. & Salapatek, A. M. Pollinex Quattro: a novel and well-tolerated, ultra short-course allergy vaccine. Expert Rev. Vaccines 5, 617–629 (2006).

    CAS  PubMed  Google Scholar 

  133. Puggioni, F., Durham, S. R. & Francis, J. N. Monophosphoryl lipid A (MPL) promotes allergen-induced immune deviation in favour of Th1 responses. Allergy 60, 678–684 (2005).

    CAS  PubMed  Google Scholar 

  134. Krieg, A. M. Therapeutic potential of Toll-like receptor 9 activation. Nature Rev. Drug Discov 5, 471–484 (2006).

    CAS  Google Scholar 

  135. Broide, D. et al. Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness. J. Immunol. 161, 7054–7062 (1998).

    CAS  PubMed  Google Scholar 

  136. Serebrisky, D. et al. CpG oligodeoxynucleotides can reverse Th2-associated allergic airway responses and alter the B7.1/B7.2 expression in a murine model of asthma. J. Immunol. 165, 5906–5912 (2000).

    CAS  PubMed  Google Scholar 

  137. Broide, D. H. et al. Systemic administration of immunostimulatory DNA sequences mediates reversible inhibition of Th2 responses in a mouse model of asthma. J. Clin. Immunol. 21, 175–182 (2001).

    CAS  PubMed  Google Scholar 

  138. Horner, A. A. et al. Immunostimulatory DNA inhibits IL-4-dependent IgE synthesis by human B cells. J. Allergy Clin. Immunol. 108, 417–423 (2001).

    CAS  PubMed  Google Scholar 

  139. Baena-Cagnani, C., Rossi, G. A. & Canonica, G. W. Airway remodelling in children: when does it start? Curr. Opin Allergy Clin. Immunol. 7, 196–200 (2007).

    PubMed  Google Scholar 

  140. Cho, J. Y. et al. Immunostimulatory DNA inhibits transforming growth factor-beta expression and airway remodeling. Am. J. Respir. Cell Mol. Biol. 30, 651–661 (2004).

    CAS  PubMed  Google Scholar 

  141. Jain, V. V. et al. Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure. Am. J. Physiol. Lung Cell Mol. Physiol. 285, 1137–1146 (2003).

    Google Scholar 

  142. Youn, C. J. et al. Immunostimulatory DNA reverses established allergen-induced airway remodeling. J. Immunol. 173, 7556–7564 (2004).

    CAS  PubMed  Google Scholar 

  143. Simons, F. E., Shikishima, Y., Van Nest, G., Eiden, J. J. & HayGlass, K. T. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA. J. Allergy Clin. Immunol. 113, 1144–1151 (2004).

    CAS  PubMed  Google Scholar 

  144. Creticos, P. S. et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N. Engl. J. Med. 355, 1445–1455 (2006).

    CAS  PubMed  Google Scholar 

  145. Tulic, M. K. et al. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J. Allergy Clin. Immunol. 113, 235–241 (2004).

    CAS  PubMed  Google Scholar 

  146. Casale, T. B. & Stokes, J. R. Immunomodulators for allergic respiratory disorders. J. Allergy Clin. Immunol. 121, 288–296 (2008).

    CAS  PubMed  Google Scholar 

  147. Nelson, H. S. et al. Daclizumab improves asthma control in patients with refractory asthma. J. Allergy Clin. Immunol. 115, S134 (2005).

    Google Scholar 

  148. Vlad, G. et al. Anti-CD25 treatment and FOXP3-positive regulatory T cells in heart transplantation. Transpl. Immunol. 18, 13–21 (2007).

    CAS  PubMed  Google Scholar 

  149. Flood-Page, P. T., Manzies-Gow, A. N., Kay, A. B. & Robinson, D. S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am. J. Respir. Crit. Care Med. 167, 199–204 (2003).

    PubMed  Google Scholar 

  150. Kips, J. C. et al. Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am. J. Respir. Crit. Care Med. 167, 1655–1659 (2003).

    PubMed  Google Scholar 

  151. Flood-Page, P. et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Invest. 112, 1029–1036 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Phipps, S., Flood-Page, P., Menzies-Gow, A., Ong, Y. E. & Kay, A. B. Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin. J. Invest. Dermatol. 122, 1406–1412 (2004).

    CAS  PubMed  Google Scholar 

  153. Andrews, A. L., Holloway, J. W., Holgate, S. T. & Davies, D. E. IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. J. Immunol. 176, 7456–7461 (2006).

    CAS  PubMed  Google Scholar 

  154. Borish, L. C. et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 160, 1816–1823 (1999).

    CAS  PubMed  Google Scholar 

  155. Borish, L. C. et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J. Allergy Clin. Immunol. 107, 963–970 (2001).

    CAS  PubMed  Google Scholar 

  156. Stein, M. L. et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J. Allergy Clin. Immunol. 118, 1312–1319 (2006).

    CAS  PubMed  Google Scholar 

  157. Liu, Y. J. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. J. Allergy Clin. Immunol. 120, 238–244 (2007).

    CAS  PubMed  Google Scholar 

  158. Medoff, B. D., Thomas, S. Y. & Luster, A. D. T cell trafficking in allergic asthma: the ins and outs. Annu. Rev. Immunol. 26, 205–232 (2008).

    CAS  PubMed  Google Scholar 

  159. Wang, Y. H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204, 1837–1847 (2007). IL- 25 (IL-17E), a distinct member of the IL-17 cytokine family, has an important role in evoking T-helper type 2 (T H 2) cell-mediated inflammation, which is characterized by infiltrations of eosinophils and T H 2 memory cells.

  160. Kang, C. M. et al. Interleukin-25 and interleukin-13 production by alveolar macrophages in response to particles. Am. J. Respir. Cell Mol. Biol. 33, 290–296 (2005).

    CAS  PubMed  Google Scholar 

  161. Dillon, S. R. et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nature Immunol. 5, 752–760 (2004). These data indicate that IL-31 is preferentially produced by T H 2 cells and signals through a receptor composed of IL-31 receptor A and oncostatin M receptor to promote dermatitis and epithelial responses.

  162. Bilsborough, J. et al. IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J. Allergy Clin. Immunol. 117, 418–425 (2006).

    CAS  PubMed  Google Scholar 

  163. Kakkar, R. & Lee, R. T. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nature Rev. Drug Discov. 7, 827–840 (2008).

    CAS  Google Scholar 

  164. Tilg, H., Moschen, A. & Kaser, A. Mode of function of biological anti-TNF agents in the treatment of inflammatory bowel diseases. Expert Opin Biol. Ther. 7, 1051–1059 (2007).

    CAS  PubMed  Google Scholar 

  165. Morjaria, J. B. et al. The role of a soluble TNFalpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 63, 584–591 (2008).

    CAS  PubMed  Google Scholar 

  166. Berry, M. A. et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N. Engl. J. Med. 354, 697–708 (2006).

    CAS  PubMed  Google Scholar 

  167. Wenzel, S. E. et al. A randomized, double-blind, placebo-controlled study of TNF-{alpha} blockade in severe persistent asthma. Am. J. Respir. Crit. Care Med. 179, 549–558 (2009).

    CAS  PubMed  Google Scholar 

  168. Kuehr, J. et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J. Allergy Clin. Immunol. 109, 274–280 (2002).

    CAS  PubMed  Google Scholar 

  169. Casale, T. B. et al. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J. Allergy Clin. Immunol. 117, 134–140 (2006).

    CAS  PubMed  Google Scholar 

  170. Jutel, M., Watanabe, T., Akdis, M., Blaser, K. & Akdis, C. A. Immune regulation by histamine. Curr. Opin Immunol. 14, 735–740 (2002).

    CAS  PubMed  Google Scholar 

  171. Thurmond, R. L., Gelfand, E. W. & Dunford, P. J. The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nature Rev. Drug Discov. 7, 41–53 (2008).

    CAS  Google Scholar 

  172. Jutel, M. et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413, 420–425 (2001).

    CAS  PubMed  Google Scholar 

  173. Muller, U. R. et al. Clinical and immunol.ogic effects of H1 antihistamine preventive medication during honeybee venom immunotherapy. J. Allergy Clin. Immunol. 122, 1001–1007 (2008).

    PubMed  Google Scholar 

  174. Allam, J. P. et al. Comparative analysis of nasal and oral mucosa dendritic cells. Allergy 61, 166–172 (2006).

    CAS  PubMed  Google Scholar 

  175. Allam, J. P. et al. Toll-like receptor 4 ligation enforces tolerogenic properties of oral mucosal Langerhans cells. J. Allergy Clin. Immunol. 121, 368–374 e361 (2008).

    CAS  PubMed  Google Scholar 

  176. Moingeon, P. et al. Immune mechanisms of allergen-specific sublingual immunotherapy. Allergy 61, 151–165 (2006).

    CAS  PubMed  Google Scholar 

  177. Rossi, R. E., Monasterolo, G., Coco, G., Silvestro, L. & Operti, D. Evaluation of serum IgG4 antibodies specific to grass pollen allergen components in the follow up of allergic patients undergoing subcutaneous and sublingual immunotherapy. Vaccine 25, 957–964 (2007).

    CAS  PubMed  Google Scholar 

  178. Burastero, S. E. et al. Effect of sublingual immunotherapy with grass monomeric allergoid on allergen-specific T-cell proliferation and interleukin 10 production. Ann. Allergy Asthma Immunol. 100, 343–350 (2008).

    CAS  PubMed  Google Scholar 

  179. Savolainen, J., Jacobsen, L. & Valovirta, E. Sublingual immunotherapy in children modulates allergen-induced in vitro expression of cytokine mRNA in PBMC. Allergy 61, 1184–1190 (2006).

    CAS  PubMed  Google Scholar 

  180. Bohle, B. et al. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J. Allergy Clin. Immunol. 120, 707–713 (2007).

    CAS  PubMed  Google Scholar 

  181. Passalacqua, G. et al. Clinical and immunol.ogic effects of a rush sublingual immunotherapy to Parietaria species: A double-blind, placebo-controlled trial. J. Allergy Clin. Immunol. 104, 964–968 (1999).

    CAS  PubMed  Google Scholar 

  182. Lue, K. H. et al. Clinical and immunol.ogic effects of sublingual immunotherapy in asthmatic children sensitized to mites: a double-blind, randomized, placebo-controlled study. Pediatr. Allergy Immunol. 17, 408–415 (2006).

    PubMed  Google Scholar 

  183. Alexander, C., Tarzi, M., Larche, M. & Kay, A. B. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects. Allergy 60, 1269–1274 (2005).

    CAS  PubMed  Google Scholar 

  184. Kundig, T. M. et al. Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. J. Allergy Clin. Immunol. 117, 1470–1476 (2006).

    PubMed  Google Scholar 

  185. Johansen, P. et al. Direct intralymphatic injection of peptide vaccines enhances immunogenicity. Eur J. Immunol. 35, 568–574 (2005).

    CAS  PubMed  Google Scholar 

  186. Senti, G. et al. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc. Natl Acad. Sci. USA 105, 17908–17912 (2008).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' laboratories are supported by the Swiss National Foundation grants 32-125249 and 32-118226, Global Allergy and Asthma European Network (GA2LEN) and Christine Kühne-Center for Allergy Research and Education, Davos (CK-CARE).

Author information

Authors and Affiliations

  1. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Obere Strasse 22, Davos Platz, CH7270, Switzerland

    Mübeccel Akdis & Cezmi A. Akdis

Authors
  1. Mübeccel Akdis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cezmi A. Akdis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cezmi A. Akdis.

Ethics declarations

Competing interests

The authors collaborate with and receive financial research support from ALK-Abello, Stallergenes S.A., Allergopharma, Joachim-Ganzer KG, ImVision AG, Societa Antica Ritrovati Medicinali and the Global Allergy and Asthma European Network (GA2LEN).

Related links

Related links

FURTHER INFORMATION

Assessment of the contribution of monophosphoryl lipid A (MPL) to a grass pollen allergy vaccine

Development of an anti-IL13 humanized mAb

Evaluation of a novel method in specific immunotherapy in cat allergic patients

Cezmi A. Akdis homepage

Glossary

Sensitization

Exposure to an allergen and development of T-cell and B-cell activation, proliferation and antibody production. It is often used to describe allergen-specific IgE.

Epitope

Antigenic determinant, a site on an antigen that is recognized by an antibody or an antigen receptor.

Clonal expansion

Production of daughter cells from a single cell.

Chemokine

Small chemoattractive proteins that stimulate the migration of cells.

Class switching

Change from one antibody class to another, for example, from an isotype called IgM to an isotype called IgG.

Effector T cells

T cells that are responsible for features of the immune response such as cell killing, cell activation (which results in clearance of pathogens, tumours, alloantigens), allergic inflammation and autoimmunity.

Helminths

Parasitic worms categorized into three groups: cestodes, nematodes and trematodes.

Apoptosis

A form of cell death in which the cell activates an internal death programme, leading to DNA degradation and nuclear condensation.

Alloantigens

An antigen produced in another member of the same species as part of an organism's self-recognition system.

Hyper IgE syndrome

Heterogeneous group of disorders characterized by recurrent staphylococcal infections, unusual eczema-like skin rashes, severe lung infections and very high concentrations of serum IgE.

Hypereosinophilia

A marked increase in eosinophil count in the bloodstream.

Immunedysregulation polyendocrinopathy enteropathy X-linked syndrome

(IPEX). A rare disorder of the immune system due to mutations in the FOXP3 gene, which results in severe autoimmune phenomena, atopic dermatitis with high levels of serum IgE and severe infections.

Peripheral tolerance

Immune tolerance acquired by mature B lymphocytes and T lymphocytes in peripheral tissues.

Antigen presentation

The display of an antigen as peptide fragments bound to major histocompatibility complex molecules on the surface of a cell to T cells.

Conformational (B cell) epitopes

Discontinuous epitopes on a protein antigen brought together by protein folding.

FEV1

Forced expiratory volume in one second.

Rush SIT

A rapid dose escalation during the dose-increase period of an allergen-SIT protocol.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Akdis, M., Akdis, C. Therapeutic manipulation of immune tolerance in allergic disease. Nat Rev Drug Discov 8, 645–660 (2009). https://doi.org/10.1038/nrd2653

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2653

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing