American Journal of Clinical Dermatology

, Volume 5, Issue 5, pp 281–294 | Cite as

The Potential Role of Allergen-Specific Sublingual Immunotherapy in Atopic Dermatitis

Leading Article

Abstract

Atopic dermatitis is a chronic inflammatory skin disease associated with increasing prevalence, morbidity, and cost in developed Western countries. Frequently associated with respiratory allergy during adulthood, atopic dermatitis often represents the first phenotypic appearance of atopy in early childhood when the allergic ‘march’ starts and progressively moves toward food allergy, asthma, and rhinitis.

At present, a consistent body of evidence supports the view that atopic dermatitis may represent the skin compartmentalization of a systemic allergic inflammation. Lymphocytes infiltrating early lesional skin express a T helper (Th) 2 pattern of cytokine secretion (increased levels of interleukin [IL]-4 and/or IL-13 and decreased levels of interferon-γ) as well as the typical Th2-type chemokine receptor CCR4, specific to the thymus and activation-regulated chemokines. Keratinocytes from patients with atopic dermatitis produce thymic stromal lymphopoietin, a novel cytokine that supports the early lymphocyte development in mouse models, and activates dendritic cells involved in the pathogenesis of allergic diseases in humans. Increased levels of circulating hemopoietic precursor cells have been reported in atopic dermatitis, as in allergic asthma and rhinitis. Furthermore, the recognition of CD34+ hemopoietic precursor cells, and evidence for cellular differentiation/ maturational events occurring within atopic dermatitis skin lesion infiltrates, are consistent with the recent reinterpretation of the Th2/Th1 paradigm, where Th2 cells appear to belong to the early stages and Th1 to the ultimate stages of a linear, rather than divergent, pattern of lymphoid differentiation.

This more detailed understanding of the immunologic derangements contributing to the atopic dermatitis pathogenesis has led to growing interest in allergen-specific immunotherapy for the disease. Due to the complexity intrinsic to atopic dermatitis and the lack of consensus-based guidelines for standardized outcome measure, only eight studies are available in the literature for a qualitative evaluation of this treatment approach. Two of these studies were double blind and placebo controlled, and six were cohort studies. Immunotherapy was found to be effective in one controlled study and five observational reports. Uncertain results were provided by one low-powered, controlled study, and negative outcomes were raised by a unique study performed with oral immunotherapy, which is not an effective route of mucosal allergen administration.

Thus, more efficacy studies are required before immunotherapy could be recommended for the routine treatment of atopic dermatitis. Allergen-specific sublingual immunotherapy, given its excellent safety profile and ability to interfere with the systemic aspects of allergic inflammation, appears a good potential candidate for the pathogenetic treatment of the disease.

References

  1. 1.
    Daniels J, Harper J. The epidemiology of atopic dermatitis. Hosp Med 2002; 63: 649–52PubMedGoogle Scholar
  2. 2.
    Oranje AP, de Waard-van der Spek FB. Atopic dermatitis: review 2000 to January 2001. Curr Opin Pediatr 2002; 14: 410–3PubMedCrossRefGoogle Scholar
  3. 3.
    Bousquet J, Van Cauwenberge P, Khaltaev N, et al. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001 Nov; 108 Suppl. 5: S147–334CrossRefGoogle Scholar
  4. 4.
    Uchida T, Suto H, Ra C, et al. Preferential expression of T(h) 2-type chemokine and its receptor in atopic dermatitis. Int Immunol 2002; 14: 1431–8PubMedCrossRefGoogle Scholar
  5. 5.
    Saurat JH. Eczema in primary immune-deficiencies: clues to the pathogenesis of atopic dermatitis with special reference to the Wiskott-Aldrich syndrome. Acta Derm Venereol 1985; 114: 125–8Google Scholar
  6. 6.
    Hanifin JM, Butler JM, Chan SC. Immunopharmacology of the atopic diseases. J Invest Dermatol 1985; 85: 161–4CrossRefGoogle Scholar
  7. 7.
    Mastrandrea F, Minardi A, Coradduzza G, et al. Atopic dermatitis: towards a plausible pathogenetic model. Ital J Allergy Clin Immunol 1998; 8: 503–17Google Scholar
  8. 8.
    Mastrandrea F, Cadario G, Bedello PG, et al. Expression of T-lineage early developmental markers by cells establishing atopic dermatitis skin infiltrates. J Investig Allergol Clin Immunol 1998; 8: 359–64PubMedGoogle Scholar
  9. 9.
    Mastrandrea F, Cadario G, Nicotra MR, et al. Hemopoietic progenitor cells in atopic dermatitis skin lesions. J Investig Allergol Clin Immunol 1999; 9: 386–91PubMedGoogle Scholar
  10. 10.
    Robert C, Kupper TS. Inflammatory skin diseases, T cell and immune surveillance. N Engl J Med 1999; 341: 1817–28PubMedCrossRefGoogle Scholar
  11. 11.
    Picker LJ, Michie SA, Rott LS, et al. A unique phenotype of skin-associated lymphocytes in humans: preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am J Pathol 1990; 136: 1053–68PubMedGoogle Scholar
  12. 12.
    Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996; 272: 60–6PubMedCrossRefGoogle Scholar
  13. 13.
    Galy AH, Cen D, Travis M, et al. Delineation of T-progenitor cell activity within the CD34+ compartment of adult bone marrow. Blood 1995; 85: 2770–8PubMedGoogle Scholar
  14. 14.
    Galy A, Morel F, Hill B, et al. Hematopoietic progenitors cells of lymphocytes and dendritic cells. J Immunother 1998; 21: 132–41PubMedCrossRefGoogle Scholar
  15. 15.
    Cerasoli DM, Kelsoe G, Sarzotti M. CD4+Thy1- thymocytes with a Th-type 2 cytokine response. Int Immunol 2001; 13: 75–83PubMedCrossRefGoogle Scholar
  16. 16.
    Kikkawa E, Yamashita M, Kimura M, et al. T(h)1/T(h)2 cell differentiation of developing CD4 single-positive thymocytes. Int Immunol 2002; 14: 943–51PubMedCrossRefGoogle Scholar
  17. 17.
    Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP. Nat Immunol 2002; 3: 637–80Google Scholar
  18. 18.
    De Vries IJ, Langeveld-Wildschut EG, Van Reijsen FC, et al. Nonspecific T-cell homing during inflammation in atopic dermatitis: expression of cutaneous lymphocyte-associated antigen and integrin αEβ7 on skin-infiltrating T-cells. J Allergy Clin Immunol 1997; 100: 694–701PubMedCrossRefGoogle Scholar
  19. 19.
    Mastrandrea F, Coradduzza G, Serio G, et al. T-cell receptor Vβ repertoire in mite-allergic subjects after sub-lingual immunotherapy. Invest Allergol Clin Immunol 2000; 10: 142–8Google Scholar
  20. 20.
    Kelso A. Th1 and Th2 subsets: paradigms lost? Immunol Today 1995; 16: 374–9PubMedCrossRefGoogle Scholar
  21. 21.
    Allen JE, Maizels RM. Th1-Th2: reliable paradigm or dangerous dogma? Immunol Today 1997; 18: 387–92PubMedCrossRefGoogle Scholar
  22. 22.
    Borish L, Rosenwasser L. TH1/TH2 lymphocytes: doubt some more. J Allergy Clin Immunol 1997; 99: 161–4PubMedCrossRefGoogle Scholar
  23. 23.
    Noble A, Kemeny DM. Do functional subsets of leukocytes arise by divergent or linear differentiation? Immunology 2002; 106: 443–6PubMedCrossRefGoogle Scholar
  24. 24.
    Codlin S, Soh C, Lee T, et al. Characterization of a palindromic enhancer element in the promoters of IL4, IL5, and IL13 cytokine genes. J Allergy Clin Immunol 2003; 111: 826–32PubMedCrossRefGoogle Scholar
  25. 25.
    Mastrandrea F. Immunotherapy in atopic dermatitis. Expert Opin Investig Drugs 2001; 10: 49–63PubMedCrossRefGoogle Scholar
  26. 26.
    Trinchieri G. Interleukin 12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen specific adaptive immunity. Annu Rev Immunol 1995; 13: 251–76PubMedCrossRefGoogle Scholar
  27. 27.
    McDyer JF, Wu CY, Seder RA. The regulation of IL12: Its role in infectious, autoimmune and allergic diseases. J Allergy Clin Immunol 1998; 102: 11–5PubMedCrossRefGoogle Scholar
  28. 28.
    Tang ML, Kemp AS, Thoburn J, et al. Reduced interferon-gamma secretion in neonates and subsequent atopy. Lancet 1994; 344: 983–5PubMedCrossRefGoogle Scholar
  29. 29.
    Warner JA, Miles EA, Jones AC, et al. Is deficiency of interferon gamma production by allergen-triggered cord blood a predictor of atopic eczema? Clin Exp Allergy 1994; 24: 423–30PubMedCrossRefGoogle Scholar
  30. 30.
    Liao SY, Liao TN, Chiang BL, et al. Decreased production of IFN gamma and increased production of IL6 by cord blood mononuclear cells of newborns with a high risk of allergy. Clin Exp Allergy 1996; 26: 397–405PubMedCrossRefGoogle Scholar
  31. 31.
    Loza MJ, Perussia B. Peripheral immature CD2-/low T cell development from type 2 to type 1 cytokine production. J Immunol 2002; 169: 3061–8PubMedGoogle Scholar
  32. 32.
    Smart JM, Tang ML, Kemp AS. Polyclonal and allergen-induced cytokine responses in children with elevated immunoglobulin E but no atopic diseases. Clin Exp Allergy 2002; 32: 1552–7CrossRefGoogle Scholar
  33. 33.
    Loza MJ, Perussia B. Final steps of natural killer cell maturation: a model for type 1- type2 differentiation. Nat Immunol 2001; 2: 917–24PubMedCrossRefGoogle Scholar
  34. 34.
    Loza MJ, Zamai L, Azzoni L, et al. Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells. Blood 2002; 99: 1273–81PubMedCrossRefGoogle Scholar
  35. 35.
    Gadue P, Stein PL. NK T cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation. J Immunol 2002; 169: 2397–406PubMedGoogle Scholar
  36. 36.
    Klangsinsirikul P, Russell NH. Peripheral blood stem cell harvested from G-CSF-stimulated donors contain a skewed Th2 CD4 phenotype and a predominance of type 2 dendritic cells. Exp Hematol 2002; 30: 495–501PubMedCrossRefGoogle Scholar
  37. 37.
    Mosca PJ, Hobeika AC, Colling K, et al. Multiple signals are required for maturation of human dendritic cells mobilized in vivo with Flt3 ligand. J Leukoc Biol 2002; 72: 546–53PubMedGoogle Scholar
  38. 38.
    Kaiser A, Bercovici N, Abastado JP, et al. Naive CD8+ T cell recruitment and proliferation are dependent on stage of dendritic cell maturation. Eur J Immunol 2003; 33: 162–71PubMedCrossRefGoogle Scholar
  39. 39.
    Ujike A, Takeda K, Nakamura A, et al. Impaired dendritic cell maturation and increased T(H)2 responses in PIR-B(-/-)mice. Nat Immunol 2002; 3: 542–8PubMedCrossRefGoogle Scholar
  40. 40.
    Aiba S, Manome H, Yoshino Y, et al. Alteration in the production of IL-10 and IL-12 and aberrant expression of CD23, CD83 and CD86 by monocytes or monocyte-derived dendritic cells from atopic dermatitis patients. Exp Dermatol 2003; 12: 86–95PubMedCrossRefGoogle Scholar
  41. 41.
    Poussier PP, Julius M. Thymus independent T cell development and selection in the intestinal epithelium. Annu Rev Immunol 1994; 12: 521–53PubMedCrossRefGoogle Scholar
  42. 42.
    Lundqvist C, Baranov V, Hammarstrom S, et al. Intra-epithelial lymphocytes: evidence for regional specialization and extrathymic T-cell maturation in the human gut epithelium. Int Immunol 1995 Sep; 7 (9): 1473–87PubMedCrossRefGoogle Scholar
  43. 43.
    Page ST, Bogatzki LY, Hamerman JA, et al. Intestinal intraepithelial lymphocytes include precursors committed to the T cell receptor alpha beta lineage. Proc Natl Acad Sci U S A 1998; 95: 9459–64PubMedCrossRefGoogle Scholar
  44. 44.
    Saito H, Kanamori Y, Takemori T, et al. Generation of intestinal T cells from progenitors residing in gut cryptopatches. Science 1998; 280: 275–8PubMedCrossRefGoogle Scholar
  45. 45.
    Antica M, Scollay R. Development of T lymphocytes at extrathymic sites. J Immunol 1999; 163: 206–11PubMedGoogle Scholar
  46. 46.
    Oida T, Suzuki K, Nanno M, et al. Role of cryptopatches in early extrathymic maturation of intestinal intraepithelial T cells. J Immunol 2000; 164: 3616–26PubMedGoogle Scholar
  47. 47.
    Guy-Grand D, Vassalli P. Gut intraepithelial lymphocyte development. Curr Opin Immunol 2002; 14: 255–9PubMedCrossRefGoogle Scholar
  48. 48.
    Guy-Grand D, Azogui O, Celli S, et al. Extrathymic T cell lymphopoiesis: ontogeny and contribution to gut intraepithelial lymphocytes in athymic and euthymic mice. J Exp Med 2003; 197: 333–41PubMedCrossRefGoogle Scholar
  49. 49.
    Denburg JA, Telizyn S, Belda A, et al. Increased numbers of circulating basophil progenitors in atopic patients. J Allergy Clin Immunol 1985; 76: 446–72CrossRefGoogle Scholar
  50. 50.
    Denburg JA, Dolovich J, Harnish D. Basophil mast cell and eosinophil growth and differentiation factors in human allergic disease. Clin Exp Allergy 1989; 19: 249–54PubMedCrossRefGoogle Scholar
  51. 51.
    Denburg JA, Woolley M, Leber B, et al. Basophil and eosinophil differentiation in allergic reaction. J Allergy Clin Immunol 1994; 94: 1135–41PubMedCrossRefGoogle Scholar
  52. 52.
    Cameron L, Christodoulopoulos P, Lavigne F, et al. Evidence for local eosinophil differentiation within allergic nasal mucosa: inhibition with soluble IL-5 receptor. J Immunol 2000; 164: 1538–45PubMedGoogle Scholar
  53. 53.
    Stirling RG, van Resen EL, Barnes PJ, et al. Interleukin-5 induces CD34(+) eosinophil progenitor mobilization and eosinophil CCR3 expression in asthma. Am J Respir Crit Care Med 2001; 164: 1403–9PubMedGoogle Scholar
  54. 54.
    Mwamtemi HH, Koike K, Kinoshita T, et al. An increase in circulating mast cell colony-forming cells in asthma. J Immunol 2001; 166: 4672–7PubMedGoogle Scholar
  55. 55.
    Kim YK, Uno M, Hamilos DL, et al. Immunolocalization of CD34 in nasal polyposis. Am J Respir Cell Mol Biol 1999; 20: 388–97PubMedGoogle Scholar
  56. 56.
    Cyr MM, Denburg JA. Systemic aspect of allergic disease: the role of the bone marrow. Curr Opin Immunol 2001; 13: 727–32PubMedCrossRefGoogle Scholar
  57. 57.
    Mastrandrea F, Minardi A, Coradduzza G, et al. Emopoiesi leucocitaria tissutale nelle malattie allergiche: rapporti con il modello patogenetico. In: Arsieni A, Tursi A, Ventura MT, editors. La terapia delle malattie allergiche. Atti dell’ VIII Congresso della Sezione A. L. della Società Italiana di Allergologia e Immunologia Clinica: Bari, 1999: 43–9Google Scholar
  58. 58.
    Denburg JA, Dolovich J, Ohtoshi T, et al. The microenvironmental differentiation hypothesis of airway inflammation. Am J Rhinol 1990; 4: 29–32CrossRefGoogle Scholar
  59. 59.
    Mastrandrea F, Coradduzza G, De Vita L, et al. CD34+ cells in peripheral blood of healthy human beings and allergic subjects: clue to acute and minimal persistent inflammation. Allergol Immunopathol (Madr) 2002; 30: 209–17Google Scholar
  60. 60.
    Dhabhar FS. Acute stress enhances while chronic stress suppresses skin immunity: the role of stress hormones and leukocyte trafficking. Ann N Y Acad Sci 2000; 917: 876–93PubMedCrossRefGoogle Scholar
  61. 61.
    Marshall Jr GD, Agarwal SK. Stress, immune regulation, and immunity: applications for asthma. Allergy Asthma Proc 2000; 21: 241–6PubMedCrossRefGoogle Scholar
  62. 62.
    Glaser R, MacCallum RC, Kaskowski BF, et al. Evidence for a shift in the Th-1 to Th-2 cytokine response associated with chronic stress and aging. J Gerontol A Biol Sci Med Sci 2001; 56: 477–82CrossRefGoogle Scholar
  63. 63.
    Elenkov IJ, Chrousos GP. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002; 966: 290–303PubMedCrossRefGoogle Scholar
  64. 64.
    Brewer JA, Kanagawa O, Sleckman BP, et al. Thymocyte apoptosis induced by T cell activation is mediated by glucocorticoids in vivo. J Immunol 2002; 169: 1837–43PubMedGoogle Scholar
  65. 65.
    Strauss G, Osen W, Debatin KM. Induction of apoptosis and modulation of activation and effector functions in T cells by immunosuppressive drugs. Clin Exp Immunol 2002; 128: 255–66PubMedCrossRefGoogle Scholar
  66. 66.
    Lill-Elghanian D, Schwartz K, King L, et al. Glucocorticoid-induced apoptosis in early B cells from human bone marrow. Exp Biol Med 2002; 227: 763–70Google Scholar
  67. 67.
    Siena S, Bregni M, Brando B, et al. Circulation of CD34+ hematopoietic stem cells in the peripheral blood of high-dose cyclophosphamide-treated patients: enhancement by intravenous recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1989; 74: 1905–14PubMedGoogle Scholar
  68. 68.
    Ciprandi G, Buscaglia S, Pesce G, et al. Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy. J Allergy Clin Immunol 1995; 96: 971–9PubMedCrossRefGoogle Scholar
  69. 69.
    Ricca V, Landi M, Ferrero P, et al. Minimal persistent inflammation is also present in patients with seasonal allergic rhinitis. J Allergy Clin Immunol 2000; 105: 54–7PubMedCrossRefGoogle Scholar
  70. 70.
    Ingordo V, D’Andria G, D’Andria C, et al. Results of atopy patch test with dust mite in adults with ‘intrinsic’ and ‘extrinsic’ atopic dermatitis. J Eur Acad Dermatol Venereol 2002; 16: 450–4PubMedCrossRefGoogle Scholar
  71. 71.
    Corbo GM, Ferrante E, Macciocci B, et al. Bronchial hyper-responsiveness in atopic dermatitis. Allergy 1989; 44: 595–8PubMedCrossRefGoogle Scholar
  72. 72.
    Salob SP, Laverty A, Atherton DJ. Bronchial hyper-responsiveness in children with atopic dermatitis. Pediatrics 1993; 91: 13–6PubMedGoogle Scholar
  73. 73.
    Majamaa H, Isolauri E. Evaluation of gut mucosal barrier: evidence for increased antigen transfer in children with atopic dermatitis. J Allergy Clin Immunol 1996; 97: 985–90PubMedCrossRefGoogle Scholar
  74. 74.
    Cantani A. The growing genetic links and the early onset of atopic diseases in children stress the unique role of the atopic march: a meta-analysis. J Invest Allergol Clin Immunol 1999; 9: 314–20Google Scholar
  75. 75.
    Gustafsson D, Sjoberg O, Foucard T. Development of allergies and asthma in infants and young children with atopic dermatitis: a prospective follow-up to 7 years of age. Allergy 2000; 55: 240–5PubMedCrossRefGoogle Scholar
  76. 76.
    Ohshima Y, Yamada A, Hiraoka M, et al. Early sensitization to house dust mite is a major risk factor for subsequent development of bronchial asthma in Japanese infants with atopic dermatitis: results of 4-year follow up study. Ann Allergy Asthma Immunol 2002; 89: 265–70PubMedCrossRefGoogle Scholar
  77. 77.
    Eichenfield LF, Hanifin JM, Beck LA, et al. Atopic dermatitis and asthma: parallels in the evolution of treatment. Pediatrics 2003; 111: 608–16PubMedCrossRefGoogle Scholar
  78. 78.
    Ramirez F. Glucocorticoids induce a Th2 response in vitro. Dev Immunol 1998; 6: 233–43PubMedCrossRefGoogle Scholar
  79. 79.
    Williams CM, Colemann JW. Induced expression of mRNA for IL-5, IL-6, TNF-alpha, MIP-2 and IFN-gamma in immunologically activated rat peritoneal mast cells: inhibition by dexamethasone and cyclosporin A. Immunology 1995; 86: 244–9PubMedGoogle Scholar
  80. 80.
    Wu CY, Wang K, McDyer JF, et al. Prostaglandin E2 and dexamethasone inhibit IL-12 receptor expression and IL-12 responsiveness. J Immunol 1998; 161: 2723–30PubMedGoogle Scholar
  81. 81.
    Visser J, van Boxel-Dezaire A, Methorst D, et al. Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro. Blood 1998; 91: 4255–64PubMedGoogle Scholar
  82. 82.
    Jabara HH, Ahern DJ, Vercelli D, et al. Hydrocortisone and IL-4 induce IgE isotype switching in human B cells. J Immunol 1991; 147: 1557–60PubMedGoogle Scholar
  83. 83.
    Zieg G, Lack G, Harbeck RJ, et al. In vivo effects of glucocorticoids on IgE production. J Allergy Clin Immunol 1994; 94: 222–30PubMedCrossRefGoogle Scholar
  84. 84.
    Akdis CA, Blesken T, Akdis M, et al. Glucocorticoids inhibit human antigen-specific and enhance total IgE and IgG4 production due to differential effects on T and B cells in vitro. Eur J Immunol 1997; 27: 2351–7PubMedCrossRefGoogle Scholar
  85. 85.
    Jabara HH, Brodeur SR, Geha RS. Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching. J Clin Invest 2001; 107: 371–8PubMedCrossRefGoogle Scholar
  86. 86.
    Barnes PJ. Corticosteroids, IgE, and atopy. J Clin Invest 2001; 107: 265–6PubMedCrossRefGoogle Scholar
  87. 87.
    Chen SS, Stanescu G, Magalski AE, et al. Cyclosporin A is an adjuvant in murine IgE antibody responses. J Immunol 1989; 142: 4225–32PubMedGoogle Scholar
  88. 88.
    Weeler DJ, Robins A, Pritchard DI, et al. Potentiation of in vitro synthesis of human IgE by cyclosporin A (CsA). Clin Exp Immunol 1995; 102: 85–90CrossRefGoogle Scholar
  89. 89.
    Nagai H, Hiyama H, Matsuo A, et al. FK-506 and cyclosporin A potentiate the IgE antibody production by contact sensitization with hapten in mice. J Pharmacol Exp Ther 1997; 283: 321–7PubMedGoogle Scholar
  90. 90.
    Kawamura N, Furuta H, Tame A, et al. Extremely high serum level of IgE during immunosuppressive therapy: paradoxical effect of cyclosporin A and tacrolimus. Int Arch Allergy Immunol 1997; 112: 422–4PubMedCrossRefGoogle Scholar
  91. 91.
    Hanifin JM, Schneider LC, Leung DYM, et al. Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol 1993; 28: 189–97PubMedCrossRefGoogle Scholar
  92. 92.
    Ellis CN, Stevens SR, Blok BK, et al. Interferon-gamma therapy reduces blood leukocyte levels in patients with atopic dermatitis: correlation with clinical improvement. Clin Immunol 1999; 92: 49–55PubMedCrossRefGoogle Scholar
  93. 93.
    Jang IG, Yang JK, Lee HJ, et al. Clinical improvement and immunohistochemical findings in severe atopic dermatitis treated with interferon gamma. J Am Acad Dermatol 2000; 42: 1033–40PubMedCrossRefGoogle Scholar
  94. 94.
    Isolauri E, Arvola T, Sutas Y, et al. Probiotics in the management of atopic eczema. Clin Exp Allergy 2000; 30: 1604–10PubMedCrossRefGoogle Scholar
  95. 95.
    Pessi T, Sutas Y, Hurme M, et al. Interleukin-10 generation in atopic children following oral Lactobacillus rhamnosus GG. Clin Exp Allergy 2000; 30: 1804–8PubMedCrossRefGoogle Scholar
  96. 96.
    Murch SH. Toll of allergy reduced by probiotics. Lancet 2001; 357: 1057–9PubMedCrossRefGoogle Scholar
  97. 97.
    Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001; 357: 1076–9PubMedCrossRefGoogle Scholar
  98. 98.
    Rosenfeldt V, Benfeldt E, Nielsen SD, et al. Effect of probiotic Lactobacillus strain in children with atopic dermatitis. J Allergy Clin Immunol 2003; 111: 389–95PubMedCrossRefGoogle Scholar
  99. 99.
    Arkwright PD, David TJ. Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001; 107: 531–4PubMedCrossRefGoogle Scholar
  100. 100.
    Wills-Karp M, Santeliz J, Karp CL. The germless theory of allergic diseases: revisiting the hygiene hypothesis. Nat Rev Immunol 2001; 1: 69–75PubMedCrossRefGoogle Scholar
  101. 101.
    Yazdanbakhsh M, Kremsner PG, van Ree R. Allergy, parasites, and hygiene hypothesis. Science 2002; 296: 490–4PubMedCrossRefGoogle Scholar
  102. 102.
    Braun-Fahrlander C. Does the ‘Hygiene Hypothesis’ provide an explanation for the relatively low prevalence of asthma in Bangladesh? Int J Epidemiol 2002; 31: 488–9PubMedCrossRefGoogle Scholar
  103. 103.
    Weiss ST. Eat dirt: the hygiene hypothesis and allergic diseases. N Engl J Med 2002; 347: 930–1PubMedCrossRefGoogle Scholar
  104. 104.
    Medzhitov R, Janeway Jr CA. Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 1997; 9: 4–9PubMedCrossRefGoogle Scholar
  105. 105.
    Anderson KV. Toll signals pathways in the innate immune response. Curr Opin Immunol 2000; 12: 13–9PubMedCrossRefGoogle Scholar
  106. 106.
    Ghosh S, May MJ, Kopp EB. NF-kB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16: 225–60PubMedCrossRefGoogle Scholar
  107. 107.
    May MJ, Ghosh S. Signal transduction through NF-kB. Immunol Today 1998; 19: 80–8PubMedCrossRefGoogle Scholar
  108. 108.
    Brightbill HD, Libraty DH, Krutzik SR, et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 1999; 285: 732–6PubMedCrossRefGoogle Scholar
  109. 109.
    Thoma-Uszynski S, Kiertscher SM, Ochoa MT, et al. Activation of toll-like receptor 2 on human dendritic cells triggers induction of IL-12 but not IL-10. J Immunol 2000; 165: 3804–10PubMedGoogle Scholar
  110. 110.
    Kubo S, Nakayama T, Matsuoka K, et al. Long term maintenance of IgE-mediated memory in mast cells in the absence of detectable serum IgE. J Immunol 2003; 170: 775–80PubMedGoogle Scholar
  111. 111.
    Mastrandrea F, Mottolese M, Maietta G, et al. The Dermatophagoides pteronyssinus native major antigen Der p II acts as polyclonal activator. Fund Clin Immunol 1995; 3: 131–8Google Scholar
  112. 112.
    Mastrandrea F, Serio G, Minelli M, et al. Specific sublingual immunotherapy in atopic dermatitis. Results of a 6-year follow-up of 35 consecutive patients. Allergol Immunopathol 2000; 28: 54–62Google Scholar
  113. 113.
    Noon L, Cantab BC. Prophylactic inoculation against hay fever. Lancet 1911; 1: 1572–3CrossRefGoogle Scholar
  114. 114.
    Canonica GW, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol 2003; 111: 437–48PubMedCrossRefGoogle Scholar
  115. 115.
    Bousquet J, Lockey R, Malling H. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. Allergy 1998 Oct; 102: 558–62Google Scholar
  116. 116.
    Malling HJ, Abreu-Nogueira J, Alvarez-Cuesta E, et al. Local immunotherapy. Allergy 1998; 53: 933–44PubMedCrossRefGoogle Scholar
  117. 117.
    Bousquet J, van Cauwenberge P, Khaltaev N, et al. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108 Suppl. 5: S147–334CrossRefGoogle Scholar
  118. 118.
    Madonini E, Agostinis F, Barra R, et al. Long-term and preventive effects of sublingual allergen-specific immunotherapy: a retrospective, multicentric study. Int J Immunopathol Pharmacol 2003; 16: 73–9PubMedGoogle Scholar
  119. 119.
    Di Rienzo V, Marcucci F, Puccinelli P, et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin Exp Allergy 2003; 33: 206–10PubMedCrossRefGoogle Scholar
  120. 120.
    Di Rienzo V, Pagani A, Parmiani S, et al. Post-marketing surveillance study on the safety of sublingual immunotherapy in pediatric patients. Allergy 1999; 54: 1110–3PubMedCrossRefGoogle Scholar
  121. 121.
    Andre C, Vatrinet C, Galvain S, et al. Safety of sublingual-swallow immunotherapy in children and adults. Int Arch Allergy Immunol 2000; 121: 229–34PubMedCrossRefGoogle Scholar
  122. 122.
    Madonini E, Agostini F, Barra R, et al. Safety and efficacy evaluation of sublingual allergen-specific immunotherapy a retrospective, multicenter study. Int J Immunopathol Pharmacol 2000; 13: 77–81PubMedGoogle Scholar
  123. 123.
    Lombardi C, Gargioni S, Melchiorre A, et al. Safety of sublingual immunotherapy with monomeric allergoid in adults: multicenter post-marketing surveillance study. Allergy 2001; 56: 989–92PubMedCrossRefGoogle Scholar
  124. 124.
    Grosclaude M, Bouillot P, Alt R, et al. Safety of various dosage regimens during induction of sublingual immunotherapy: a preliminary study. Int Arch Allergy Immunol 2002; 129: 248–53PubMedCrossRefGoogle Scholar
  125. 125.
    Marcucci F, Sensi L, Frati F, et al. Sublingual tryptase and ECP in children treated with grass pollen sublingual immunotherapy (SLIT): safety and immunologic implications. Allergy 2001; 56: 1091–5PubMedCrossRefGoogle Scholar
  126. 126.
    Longley BJ, Tyrrel L, Lu S, et al. Chronically KIT-stimulated clonally-derived human mast cells show heterogeneity in different tissue microenvironments. J Invest Dermatol 1997; 108: 792–6PubMedCrossRefGoogle Scholar
  127. 127.
    Peng Q, McEuen AR, Benyon RC, et al. The heterogeneity of mast cell tryptase from human lung and skin. Eur J Biochem 2003; 270: 270–83PubMedCrossRefGoogle Scholar
  128. 128.
    Bagnasco M, Mariani M, Passalacqua G, et al. Absorption and distribution kinetics of the major Parietaria judaica allergen (Par j 1) administered by noninjectable routes in healthy human beings. J Allergy Clin Immunol 1997; 100: 122–9PubMedCrossRefGoogle Scholar
  129. 129.
    Bagnasco M, Passalacqua G, Villa G. Parmacokinetiks of an allergen and a monomeric allergoid for oromucosal immunotherapy in allergic volunteers. Clin Exp Allergy 2001; 31: 54–60PubMedCrossRefGoogle Scholar
  130. 130.
    Ino Y, Ando T, Haida M, et al. Characterization of the proteases in the crude mite extract. Int Arch Allergy Appl Immunol 1989; 89: 321–6PubMedCrossRefGoogle Scholar
  131. 131.
    Hakkaart GA, Aalberse RC, van Ree R. Lack of lysozyme activity of natural and yeast-derived recombinant Der p 2. Int Arch Allergy Immunol 1997; 114: 202–4PubMedCrossRefGoogle Scholar
  132. 132.
    Chua KY, Stewart GA, Thomas WR, et al. Sequence analysis of cDNA coding for a major house dust mite allergen, Der p 1. Homology with cysteine proteases. J Exp Med 1988; 167: 175–82PubMedCrossRefGoogle Scholar
  133. 133.
    Mastrandrea F, Nicotra MR, De Vita L, et al. Mite antigens enhance ICAM-1 and induce VCAM-1 expression on Human Umbilical Vein Endothelium. Allergol Immunopathol 2003 Sep-Oct; 31 (5): 259–64CrossRefGoogle Scholar
  134. 134.
    Stacey MA, Sun G, Vassalli G, et al. The allergen Der p1 induces NF-kappaB activation through interference with IkappaB alpha function in asthmatic bronchial epithelial cells. Biochem Biophys Res Commun 1997; 236: 522–6PubMedCrossRefGoogle Scholar
  135. 135.
    Mitsuta K, Matsuse H, Fukushima C, et al. Production of TNF-alpha by peripheral blood mononuclear cells through activation of nuclear factor Kappa B by specific allergen stimulation in patients with atopic dermatitis. Allergy Asthma Proc 2003; 24: 19–26PubMedGoogle Scholar
  136. 136.
    Chen CL, Lee CT, Liu YC, et al. House dust mite Dermatophagoides farinae augments proinflammatory mediator production and accessory function of alveolar macrophages: implications for allergic sensitization and inflammation. J Immunol 2003; 170: 528–36PubMedGoogle Scholar
  137. 137.
    Collins T, Read MA, Neish AS, et al. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J 1995; 9: 899–909PubMedGoogle Scholar
  138. 138.
    Chen CC, Manning AM. Transcriptional regulation of endothelial cell adhesion molecules: a dominant role for NF-Kappa B. Agents Actions Suppl 1995; 47: 135–41PubMedGoogle Scholar
  139. 139.
    Franco L, Benedetti R, Ferek GA, et al. Priming or tolerization of the B- and Th2-dependent immune response by the oral administration of OVA-DNP is determined by the antigen dosage. Cell Immunol 1998; 190: 1–11PubMedCrossRefGoogle Scholar
  140. 140.
    Chung Y, Chang SY, Kang CY. Kinetic analysis of oral tolerance: memory lymphocytes are refractory to oral tolerance. J Immunol 1999; 163: 3692–8PubMedGoogle Scholar
  141. 141.
    Shi HN, Grusby MJ, Nagler-Anderson C. Orally induced peripheral nonresponsiveness is maintained in the absence of functional Th1 or Th2 cells. J Immunol 1999; 162: 5143–8PubMedGoogle Scholar
  142. 142.
    Fanta C, Bohle B, Hirt W, et al. Systemic immunological changes induced by administration of grass pollen allergens via the oral mucosa during sublingual immunotherapy. Int Arch Allergy Immunol 1999; 120: 218–24PubMedCrossRefGoogle Scholar
  143. 143.
    Marth T, Ring S, Schulte D, et al. Antigen-induced mucosal T cell activation is followed by Th1 T cell suppression in continuously fed ovalbumin TCR-transgenic mice. Eur J Immunol 2000; 30: 3478–86PubMedCrossRefGoogle Scholar
  144. 144.
    Sato MN, Fusaro AE, Victor JR, et al. Oral tolerance induction in Dermatophagoides pteronyssinus-sensitized mice induces inhibition of IgE response and upregulation of TGF-beta secretion. J Interferon Cytokine Res 2001; 21: 827–33PubMedCrossRefGoogle Scholar
  145. 145.
    Boonstra A, Asselin-Paturel C, Gilliet M, et al. Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. J Exp Med 2003; 197: 101–9PubMedCrossRefGoogle Scholar
  146. 146.
    Izon D, Rudd K, DeMuth W, et al. A common pathway for dendritic and early B cell development. J Immunol 2001; 167: 1387–92PubMedGoogle Scholar
  147. 147.
    Glover MT, Atherton DJ. A double-blind controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with atopic eczema. Clin Exp Allergy 1992; 22: 440–6PubMedCrossRefGoogle Scholar
  148. 148.
    Leroy BP, Boden G, Lachapelle JM, et al. A novel therapy for atopic dermatitis with allergen-antibody complexes: a double-blind, placebo-controlled study. J Am Acad Dermatol 1993; 28: 232–9PubMedCrossRefGoogle Scholar
  149. 149.
    Pacor ML, Biasi D, Maleknia T. The efficacy of long-term specific immunotherapy for Dermatophagoides pteronyssinus in patients with atopic dermatitis. Recenti Prog Med 1994; 85: 273–7PubMedGoogle Scholar
  150. 150.
    Trofimowicz A, Rzepcka E, Hofman J. Clinical effect of specific immunotherapy in children with atopic dermatitis. Rocz Akad Med Bialymist 1995; 40: 414–22Google Scholar
  151. 151.
    Galli E, Chini L, Nardi S, et al. Use of oral hyposensitization therapy to Dermatophagoides pteronyssinus in children with atopic dermatitis. Allergol Immunopathol 1994; 22: 18–22Google Scholar
  152. 152.
    Mosca M, Albani-Ronchetti G, Vignini MA, et al. La vaccinoterapia sub-linguale nella dermatite atopica. G. Ital Dermatol Venereol 1993; 128: 79–83Google Scholar
  153. 153.
    Zwacka G, Glaser S, Rieger B. Therapeutische erfahrungen mit Pangramin-SLIT im verleich zu einer subkutanen immunotherapie und zur symptomatischen medikamentosen behandlung bei kindern mit asthma bronchiale, rhinokonjunctivitis und atopischer dermatitis. Allergologie 1996; 19: 580–92Google Scholar
  154. 154.
    Petrova SIu, Berzhets VM, Albanova VI, et al. Immunotherapy in the complex treatment of patients with atopic dermatitis with sensitization to house dust mites. Zh Mikrobiol Epidemiol Immunobiol 2001; 1: 33–6PubMedGoogle Scholar
  155. 155.
    Boquete M, Carballada F, Exposito F, et al. Preventive immunotherapy. Allergol Immunopathol 2000; 28: 89–93Google Scholar
  156. 156.
    Pajno GB, Barberio G, De Luca F, et al. Prevention of new sensitisations in asthmatic children monosensitized to house dust mite by specific immunotherapy: a six-year follow-up study. Clin Exp Allergy 2001; 31: 1392–7PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.SSD Allergy and Clinical Immunology Operative UnitAUSL TA1 SS Annunziata Hospital, via BrunoTarantoItaly

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