Immunosuppressants as Treatment for Atopic Dermatitis

  • Bartlomiej Kwiek
  • Natalija Novak
Part of the Allergy Frontiers book series (ALLERGY, volume 5)

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting about 20% of children and up to 3% of adults worldwide. The clinical manifestation of AD is based on the interaction of specific genetic predispositions with a large number of environmental factors. Treatment of AD depends on the course and severity of the disease as well as the most important trigger factors such as aero- or foodallergens, microbial pathogens or other exogenous and endogenous influences [1]. Here we provide an overview of the mode of action of different immunosuppressants, which are frequently used as treatment for AD.


Atopic Dermatitis Allergy Clin Immunol Atopic Dermatitis Patient Severe Atopic Dermatitis Tacrolimus Ointment 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Leung DY, Bieber T (2003) Atopic dermatitis. Lancet 361:151–160PubMedCrossRefGoogle Scholar
  2. 2.
    Sternberg TH, Newcomer VD, Linden IH (1952) Treatment of atopic dermatitis with cortisone. J Am Med Assoc 148:904–907PubMedGoogle Scholar
  3. 3.
    Sulzberger MB, Witten VH (1952) The effect of topically applied compound F in selected dermatoses. J Invest Dermatol 19:101–102PubMedGoogle Scholar
  4. 4.
    Akdis CA, Akdis M, Bieber T, Bindslev-Jensen C, Boguniewicz M, Eigenmann P, Hamid Q, Kapp A, Leung DY, Lipozencic J, Luger TA, Muraro A, Novak N, Platts-Mills TA, Rosenwasser L, Scheynius A, Simons FE, Spergel J, Turjanmaa K, Wahn U, Weidinger S, Werfel T, Zuberbier T (2006) Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy 61:969–987PubMedCrossRefGoogle Scholar
  5. 5.
    Pratt WB, Galigniana MD, Morishima Y, Murphy PJ (2004) Role of molecular chaperones in steroid receptor action. Essays Biochem 40:41–58PubMedGoogle Scholar
  6. 6.
    Wu B, Li P, Liu Y, Lou Z, Ding Y, Shu C, Ye S, Bartlam M, Shen B, Rao Z (2004) 3D structure of human FK506-binding protein 52: implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin heterocomplex. Proc Natl Acad Sci USA 101:8348–8353PubMedCrossRefGoogle Scholar
  7. 7.
    Leung DY, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, Chrousos GP, Klemm DJ (1997) Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med 186:1567–1574PubMedCrossRefGoogle Scholar
  8. 8.
    Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids-new mechanisms for old drugs. N Engl J Med 353:1711–1723PubMedCrossRefGoogle Scholar
  9. 9.
    Barnes PJ (2006) How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol 148:245–254PubMedCrossRefGoogle Scholar
  10. 10.
    Ismaili N, Garabedian MJ (2004) Modulation of glucocorticoid receptor function via phos-phorylation. Ann N Y Acad Sci 1024:86–101PubMedCrossRefGoogle Scholar
  11. 11.
    Mozo L, Suarez A, Gutierrez C (2004) Glucocorticoids up-regulate constitutive interleukin-10 production by human monocytes. Clin Exp Allergy 34:406–412PubMedCrossRefGoogle Scholar
  12. 12.
    Falkenstein E, Norman AW, Wehling M (2000) Mannheim classification of nongenomically initiated (rapid) steroid action(s). J Clin Endocrinol Metab 85:2072–2075PubMedCrossRefGoogle Scholar
  13. 13.
    Long F, Wang YX, Liu L, Zhou J, Cui RY, Jiang CL (2005) Rapid nongenomic inhibitory effects of glucocorticoids on phagocytosis and superoxide anion production by macrophages. Steroids 70:55–61PubMedCrossRefGoogle Scholar
  14. 14.
    Almawi W Y, Melemedjian OK, Rieder MJ (1999) An alternate mechanism of glucocorticoid anti-proliferative effect: promotion of a Th2 cytokine-secreting profile. Clin Transplant 13:365–374PubMedCrossRefGoogle Scholar
  15. 15.
    Blotta MH, DeKruyff RH, Umetsu DT (1997) Corticosteroids inhibit IL-12 production in human monocytes and enhance their capacity to induce IL-4 synthesis in CD4+ lymphocytes. J Immunol 158:5589–5595PubMedGoogle Scholar
  16. 16.
    Dozmorov IM, Miller RA (1998) Generation of antigen-specific Th2 cells from unprimed mice in vitro: effects of dexamethasone and anti-IL-10 antibody. J Immunol 160:2700–2705PubMedGoogle Scholar
  17. 17.
    Franchimont D, Galon J, Gadina M, Visconti R, Zhou Y, Aringer M, Frucht DM, Chrousos GP, O'Shea JJ (2000) Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes. J Immunol 164:1768–1774PubMedGoogle Scholar
  18. 18.
    Liberman AC, Refojo D, Druker J, Toscano M, Rein T, Holsboer F, Arzt E (2007) The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction. FASEB J 21:1177–1188PubMedCrossRefGoogle Scholar
  19. 19.
    Miyaura H, Iwata M (2002) Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 168:1087–1094PubMedGoogle Scholar
  20. 20.
    Zieg G, Lack G, Harbeck RJ, Gelfand EW, Leung DY (1994) In vivo effects of glucocorti-coids on IgE production. J Allergy Clin Immunol 94:222–230PubMedCrossRefGoogle Scholar
  21. 21.
    Langeveld-Wildschut EG, Riedl H, Thepen T, Bihari IC, Bruijnzeel PL, Bruijnzeel-Koomen CA (2000) Modulation of the atopy patch test reaction by topical corticosteroids and tar. J Allergy Clin Immunol 106:737–743PubMedCrossRefGoogle Scholar
  22. 22.
    Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O'Shea JJ, Chrousos GP, Bornstein SR (2002) Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 16:61–71PubMedCrossRefGoogle Scholar
  23. 23.
    Hawrylowicz CM, Guida L, Paleolog E (1994) Dexamethasone up-regulates granulocyte-macrophage colony-stimulating factor receptor expression on human monocytes. Immunology 83:274–280PubMedGoogle Scholar
  24. 24.
    Gosset P, Lamblin-Degros C, Tillie-Leblond I, Charbonnier AS, Joseph M, Wallaert B, Kochan JP, Tonnel AB (2001) Modulation of high-affinity IgE receptor expression in blood monocytes: opposite effect of IL-4 and glucocorticoids. J Allergy Clin Immunol 107:114–122PubMedCrossRefGoogle Scholar
  25. 25.
    Young JD, Lawrence AJ, MacLean AG, Leung BP, McInnes IB, Canas B, Pappin DJ, Stevenson RD (1999) Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nat Med 5:1424–1427PubMedCrossRefGoogle Scholar
  26. 26.
    Karagiannidis C, Akdis M, Holopainen P, Woolley NJ, Hense G, Ruckert B, Mantel PY, Menz G, Akdis CA, Blaser K, Schmidt-Weber CB (2004) Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114:1425–1433PubMedCrossRefGoogle Scholar
  27. 27.
    Akdis M, Blaser K, Akdis CA (2006) T regulatory cells in allergy. Chem Immunol Allergy 91:159–173PubMedCrossRefGoogle Scholar
  28. 28.
    Verhagen J, Akdis M, Traidl-Hoffmann C, Schmid-Grendelmeier P, Hijnen D, Knol EF, Behrendt H, Blaser K, Akdis CA (2006) Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol 117:176–183PubMedCrossRefGoogle Scholar
  29. 29.
    Caproni M, Torchia D, Antiga E, Volpi W, del BE, Fabbri P (2006) The effects of tacrolimus ointment on regulatory T lymphocytes in atopic dermatitis. J Clin Immunol 26:370–375PubMedCrossRefGoogle Scholar
  30. 30.
    Belsito DV, Flotte TJ, Lim HW, Baer RL, Thorbecke GJ, Gigli I (1982) Effect of glucocorti-costeroids on epidermal Langerhans cells. J Exp Med 155:291–302PubMedCrossRefGoogle Scholar
  31. 31.
    Hoetzenecker W, Ecker R, Kopp T, Stuetz A, Stingl G, Elbe-Burger A (2005) Pimecrolimus leads to an apoptosis-induced depletion of T cells but not Langerhans cells in patients with atopic dermatitis. J Allergy Clin Immunol 115:1276–1283PubMedCrossRefGoogle Scholar
  32. 32.
    Schuller E, Oppel T, Bornhovd E, Wetzel S, Wollenberg A (2004) Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis. J Allergy Clin Immunol 114:137–143PubMedCrossRefGoogle Scholar
  33. 33.
    Novak N, Kraft S, Haberstok J, Geiger E, Allam P, Bieber T (2002) A reducing microenvironment leads to the generation of FcepsilonRIhigh inflammatory dendritic epidermal cells (IDEC). J Invest Dermatol 119:842–849PubMedCrossRefGoogle Scholar
  34. 34.
    Palucka AK, Banchereau J (2006) Langerhans cells: daughters of monocytes. Nat Immunol 7:223–224PubMedCrossRefGoogle Scholar
  35. 35.
    Fauci AS, Dale DC, Balow JE (1976) Glucocorticosteroid therapy: mechanisms of action and clinical considerations. Ann Intern Med 84:304–315PubMedGoogle Scholar
  36. 36.
    Kalthoff FS, Chung J, Musser P, Stuetz A (2003) Pimecrolimus does not affect the differentiation, maturation and function of human monocyte-derived dendritic cells, in contrast to corticosteroids. Clin Exp Immunol 133:350–359PubMedCrossRefGoogle Scholar
  37. 37.
    Schmidt M, Pauels HG, Lugering N, Lugering A, Domschke W, Kucharzik T (1999) Glucocorticoids induce apoptosis in human monocytes: potential role of IL-1 beta. J Immunol 163:3484–3490PubMedGoogle Scholar
  38. 38.
    Baumer W, Seegers U, Braun M, Tschernig T, Kietzmann M (2004) TARC and RANTES, but not CTACK, are induced in two models of allergic contact dermatitis. Effects of cilomilast and diflorasone diacetate on T-cell-attracting chemokines. Br J Dermatol 151:823–830PubMedCrossRefGoogle Scholar
  39. 39.
    Kakinuma T, Nakamura K, Wakugawa M, Yano S, Saeki H, Torii H, Komine M, Asahina A, Tamaki K (2002) IL-4, but not IL-13, modulates TARC (thymus and activation-regulated chemokine)/CCL17 and IP-10 (interferon-induced protein of 10kDA)/CXCL10 release by TNF-alpha and IFN-gamma in HaCaT cell line. Cytokine 20:1–6PubMedCrossRefGoogle Scholar
  40. 40.
    Masuda K, Katoh N, Okuda F, Kishimoto S (2003) Increased levels of serum interleukin-16 in adult type atopic dermatitis. Acta Derm Venereol 83:249–253PubMedCrossRefGoogle Scholar
  41. 41.
    Wollenberg A, Wagner M, Gunther S, Towarowski A, Tuma E, Moderer M, Rothenfusser S, Wetzel S, Endres S, Hartmann G (2002) Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 119:1096–1102PubMedCrossRefGoogle Scholar
  42. 42.
    Novak N, Allam JP, Hagemann T, Jenneck C, Laffer S, Valenta R, Kochan J, Bieber T (2004) Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis. J Allergy Clin Immunol 114:364–370PubMedCrossRefGoogle Scholar
  43. 43.
    Stary G, Bangert C, Stingl G, Kopp T (2005) Dendritic cells in atopic dermatitis: expression of FcepsilonRI on two distinct inflammation-associated subsets. Int Arch Allergy Immunol 138:278–290PubMedCrossRefGoogle Scholar
  44. 44.
    Hoetzenecker W, Meindl S, Stuetz A, Stingl G, Elbe-Burger A (2006) Both pimecrolimus and corticosteroids deplete plasmacytoid dendritic cells in patients with atopic dermatitis. J Invest Dermatol 126:2141–2144PubMedCrossRefGoogle Scholar
  45. 45.
    Oldhoff JM, Knol EF, Laaper-Ertmann M, Bruijnzeel-Koomen CA, de Bruin-Weller MS (2006) Modulation of the atopy patch test: tacrolimus 0.1% compared with triamcinolone acetonide 0.1%. Allergy 61:622–628PubMedCrossRefGoogle Scholar
  46. 46.
    Aziz KE, Wakefield D (1996) Modulation of endothelial cell expression of ICAM-1, E-selectin, and VCAM-1 by beta-estradiol, progesterone, and dexamethasone. Cell Immunol 167:79–85PubMedCrossRefGoogle Scholar
  47. 47.
    Caproni M, Torchia D, Antiga E, Volpi W, Fabbri P (2006) Expression of adhesion molecules in atopic dermatitis is reduced by tacrolimus, but not by hydrocortisone butyrate: a randomized immunohistochemical study. Clin Exp Dermatol 31:813–817PubMedCrossRefGoogle Scholar
  48. 48.
    Cronstein BN, Kimmel SC, Levin RI, Martiniuk F, Weissmann G (1992) A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci USA 89:9991–9995PubMedCrossRefGoogle Scholar
  49. 49.
    Furukawa H, Nakamura K, Zheng X, Tojo M, Oyama N, Akiba H, Nishibu A, Kaneko F, Tsunemi Y, Saeki H, Tamaki K (2004) Enhanced TARC production by dust-mite allergens and its modulation by immunosuppressive drugs in PBMCs from patients with atopic dermatitis. J Dermatol Sci 35:35–42PubMedCrossRefGoogle Scholar
  50. 50.
    Vestergaard C, Yoneyama H, Murai M, Nakamura K, Tamaki K, Terashima Y, Imai T, Yoshie O, Irimura T, Mizutani H, Matsushima K (1999) Overproduction of Th2-specific chemokines in NC/Nga mice exhibiting atopic dermatitis-like lesions. J Clin Invest 104:1097–1105PubMedCrossRefGoogle Scholar
  51. 51.
    Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H, Torii H, Komine M, Asahina A, Tamaki K (2002) Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clin Exp Immunol 127:270–273PubMedCrossRefGoogle Scholar
  52. 52.
    Fujisawa T, Fujisawa R, Kato Y, Nakayama T, Morita A, Katsumata H, Nishimori H, Iguchi K, Kamiya H, Gray PW, Chantry D, Suzuki R, Yoshie O (2002) Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis. J Allergy Clin Immunol 110:139–146PubMedCrossRefGoogle Scholar
  53. 53.
    Abe M, Thomson AW (2006) Dexamethasone preferentially suppresses plasmacytoid dendritic cell differentiation and enhances their apoptotic death. Clin Immunol 118:300–306PubMedCrossRefGoogle Scholar
  54. 54.
    Amsterdam A, Tajima K, Sasson R (2002) Cell-specific regulation of apoptosis by glucocor-ticoids: implication to their anti-inflammatory action. Biochem Pharmacol 64:843–850PubMedCrossRefGoogle Scholar
  55. 55.
    Trautmann A, Altznauer F, Akdis M, Simon HU, Disch R, Brocker EB, Blaser K, Akdis CA (2001) The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J Invest Dermatol 117:927–934PubMedCrossRefGoogle Scholar
  56. 56.
    Trautmann A, Akdis M, Schmid-Grendelmeier P, Disch R, Brocker EB, Blaser K, Akdis CA (2001) Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis. J Allergy Clin Immunol 108:839–846PubMedCrossRefGoogle Scholar
  57. 57.
    Xhauflaire-Uhoda E, Thirion L, Pierard-Franchimont C, Pierard GE (2007) Comparative effect of tacrolimus and betamethasone valerate on the passive sustainable hydration of the stratum corneum in atopic dermatitis. Dermatology 214:328–332PubMedCrossRefGoogle Scholar
  58. 58.
    Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY (2007) J Allergy Clin Immunol 120:150–155PubMedCrossRefGoogle Scholar
  59. 59.
    Gong JQ, Lin L, Lin T, Hao F, Zeng FQ, Bi ZG, Yi D, Zhao B (2006) Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 155:680–687PubMedCrossRefGoogle Scholar
  60. 60.
    Cho SH, Strickland I, Boguniewicz M, Leung DY (2001) Fibronectin and fibrinogen contribute to the enhanced binding of Staphylococcus aureus to atopic skin. J Allergy Clin Immunol 108:269–274PubMedCrossRefGoogle Scholar
  61. 61.
    Remitz A, Kyllonen H, Granlund H, Reitamo S (2001) Tacrolimus ointment reduces staphy-lococcal colonization of atopic dermatitis lesions. J Allergy Clin Immunol 107:196–197PubMedCrossRefGoogle Scholar
  62. 62.
    Hauk PJ, Hamid QA, Chrousos GP, Leung DY (2000) Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol 105:782–787PubMedCrossRefGoogle Scholar
  63. 63.
    Li LB, Goleva E, Hall CF, Ou LS, Leung DY (2004) Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J Allergy Clin Immunol 114:1059–1069PubMedCrossRefGoogle Scholar
  64. 64.
    Kanbe T, Soma Y, Kawa Y, Kashima M, Mizoguchi M (2001) Serum levels of soluble stem cell factor and soluble KIT are elevated in patients with atopic dermatitis and correlate with the disease severity. Br J Dermatol 144:1148–1153PubMedCrossRefGoogle Scholar
  65. 65.
    Lavker RM, Schechter NM (1985) Cutaneous mast cell depletion results from topical corti-costeroid usage. J Immunol 135:2368–2373PubMedGoogle Scholar
  66. 66.
    Mori A, Kaminuma O, Suko M, Mikami T, Nishizaki Y, Ohmura T, Hoshino A, Asakura Y, Miyazawa K, Ando T, Okumura Y, Yamamoto K, Okudaira H (1997) Cellular and molecular mechanisms of IL-5 synthesis in atopic diseases: a study with allergen-specific human helper T cells. J Allergy Clin Immunol 100:S56–S64PubMedCrossRefGoogle Scholar
  67. 67.
    Wedi B, Raap U, Lewrick H, Kapp A (1997) Delayed eosinophil programmed cell death in vitro: a common feature of inhalant allergy and extrinsic and intrinsic atopic dermatitis. J Allergy Clin Immunol 100:536–543PubMedCrossRefGoogle Scholar
  68. 68.
    Kagami S, Saeki H, Komine M, Kakinuma T, Tsunemi Y, Nakamura K, Sasaki K, Asahina A, Tamaki K (2005) Interleukin-4 and interleukin-13 enhance CCL26 production in a human keratinocyte cell line, HaCaT cells. Clin Exp Immunol 141:459–466PubMedCrossRefGoogle Scholar
  69. 69.
    Juan M, Mullol J, Roca-Ferrer J, Fuentes M, Perez M, Vilardell C, Yague J, Picado C (1999) Regulation of ICAM-3 and other adhesion molecule expressions on eosinophils in vitro. Effects of dexamethasone. Allergy 54:1293–1298Google Scholar
  70. 70.
    Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Pentlow BD, Rolles K (1978) Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 2:1323–1327PubMedCrossRefGoogle Scholar
  71. 71.
    Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR (1989) Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science 246:1617–1620PubMedCrossRefGoogle Scholar
  72. 72.
    Harper JI, Ahmed I, Barclay G, Lacour M, Hoeger P, Cork MJ, Finlay AY, Wilson NJ, Graham-Brown RA, Sowden JM, Beard AL, Sumner MJ, Berth-Jones J (2000) Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 142:52–58PubMedCrossRefGoogle Scholar
  73. 73.
    Hijnen DJ, ten BO, Timmer-de ML, Bruijnzeel-Koomen CA, de Bruin-Weller MS (2007) Efficacy and safety of long-term treatment with cyclosporin A for atopic dermatitis. J Eur Acad Dermatol Venereol 21:85–89PubMedCrossRefGoogle Scholar
  74. 74.
    Maintz L, Novak N (2007) Getting more and more complex: the pathophysiology of atopic eczema. Eur J Dermatol 17:267–283PubMedGoogle Scholar
  75. 75.
    van JT, Kozel MM, Tank B, Troost R, Prens EP (1992) Cyclosporine in atopic dermatitis. Modulation in the expression of immunologic markers in lesional skin. J Am Acad Dermatol 27:922–928CrossRefGoogle Scholar
  76. 76.
    Bunikowski R, Gerhold K, Brautigam M, Hamelmann E, Renz H, Wahn U (2001) Effect of low-dose cyclosporin a microemulsion on disease severity, interleukin-6, interleukin-8 and tumor necrosis factor alpha production in severe pediatric atopic dermatitis. Int Arch Allergy Immunol 125:344–348PubMedCrossRefGoogle Scholar
  77. 77.
    Jahnz-Rozyk K, Targowski T, Paluchowska E, Owczarek W, Kucharczyk A (2005) Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis. Allergy 60:685–688PubMedCrossRefGoogle Scholar
  78. 78.
    Campbell JJ, O'Connell DJ, Wurbel MA (2007) Cutting Edge: Chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions. J Immunol 178:3358–3362PubMedGoogle Scholar
  79. 79.
    Yamashita U, Kuroda E (2002) Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol 22:105–114PubMedGoogle Scholar
  80. 80.
    Hijnen D, De Bruin-Weller M, Oosting B, Lebre C, De JE, Bruijnzeel-Koomen C, Knol E (2004) Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell-attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis. J Allergy Clin Immunol 113:334–340PubMedCrossRefGoogle Scholar
  81. 81.
    Caproni M, Salvatore E, Cardinali C, Brazzini B, Fabbri P (2000) Soluble CD30 and cyclosporine in severe atopic dermatitis. Int Arch Allergy Immunol 121:324–328PubMedCrossRefGoogle Scholar
  82. 82.
    Bottari V, Frezzolini A, Ruffelli M, Puddu P, Fontana L, De PO (1999) Cyclosporin A (CyA) reduces sCD30 serum levels in atopic dermatitis: a possible new immune intervention. Allergy 54:507–510PubMedCrossRefGoogle Scholar
  83. 83.
    Yamada H, Kurashimo S, Chihara J, Matsukura M, Yudate T, Tezuka T (1999) Overexpression of CD11b on eosinophils in atopic dermatitis: downregulation by cyclosporin A and upregulation by interleukin 5. Int Arch Allergy Immunol 120 Suppl 1:100–103CrossRefGoogle Scholar
  84. 84.
    Kagi MK, Joller-Jemelka H, Wuthrich B (1999) Soluble E-selectin correlates with disease activity in cyclosporin A-treated patients with atopic dermatitis. Allergy 54:57–63PubMedCrossRefGoogle Scholar
  85. 85.
    Farrell AM, Antrobus P, Simpson D, Powell S, Chapel HM, Ferry BL (2001) A rapid flow cytometric assay to detect CD4+ and CD8+ T-helper (Th) 0, Th1 and Th2 cells in whole blood and its application to study cytokine levels in atopic dermatitis before and after cyclosporin therapy. Br J Dermatol 144:24–33PubMedCrossRefGoogle Scholar
  86. 86.
    Valenta R, Natter S, Seiberler S, Roschanak M, Mothes N, Mahler V, Eibensteiner P (1999) Autoallergy: a pathogenetic factor in atopic dermatitis? Curr Probl Dermatol 28:45–50PubMedCrossRefGoogle Scholar
  87. 87.
    Seiberler S, Bugajska-Schretter A, Hufnagl P, Binder BR, Stockl J, Spitzauer S, Valent P, Valenta R (1999) Characterization of IgE-reactive autoantigens in atopic dermatitis. 1. Subcellular distribution and tissue-specific expression. Int Arch Allergy Immunol 120:108–116PubMedCrossRefGoogle Scholar
  88. 88.
    Ochs RL, Muro Y, Si Y, Ge H, Chan EK, Tan EM (2000) Autoantibodies to DFS 70 kd/tran-scription coactivator p75 in atopic dermatitis and other conditions. J Allergy Clin Immunol 105:1211–1220PubMedCrossRefGoogle Scholar
  89. 89.
    Mothes N, Niggemann B, Jenneck C, Hagemann T, Weidinger S, Bieber T, Valenta R, Novak N (2005) The cradle of IgE autoreactivity in atopic eczema lies in early infancy. J Allergy Clin Immunol 116:706–709PubMedCrossRefGoogle Scholar
  90. 90.
    Kinaciyan T, Natter S, Kraft D, Stingl G, Valenta R (2002) IgE autoantibodies monitored in a patient with atopic dermatitis under cyclosporin A treatment reflect tissue damage. J Allergy Clin Immunol 109:717–719PubMedCrossRefGoogle Scholar
  91. 91.
    Rusnak F, Mertz P (2000) Calcineurin: form and function. Physiol Rev 80:1483–1521PubMedGoogle Scholar
  92. 92.
    Schiene-Fischer C, Yu C (2001) Receptor accessory folding helper enzymes: the functional role of peptidyl prolyl cis/trans isomerases. FEBS Lett 495:1–6PubMedCrossRefGoogle Scholar
  93. 93.
    Dumont FJ (2000) FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem 7:731–748PubMedGoogle Scholar
  94. 94.
    Simon D, Vassina E, Yousefi S, Kozlowski E, Braathen LR, Simon HU (2004) Reduced dermal infiltration of cytokine-expressing inflammatory cells in atopic dermatitis after short-term topical tacrolimus treatment. J Allergy Clin Immunol 114:887–895PubMedCrossRefGoogle Scholar
  95. 95.
    Simon D, Vassina E, Yousefi S, Braathen LR, Simon HU (2005) Inflammatory cell numbers and cytokine expression in atopic dermatitis after topical pimecrolimus treatment. Allergy 60:944–951PubMedCrossRefGoogle Scholar
  96. 96.
    Migita K, Eguchi K (2001) FK 506-mediated T-cell apoptosis induction. Transplant Proc 33:2292–2293PubMedCrossRefGoogle Scholar
  97. 97.
    Reich K, Hugo S, Middel P, Blaschke V, Heine A, Gutgesell C, Williams R, Neumann C (2002) Evidence for a role of Langerhans cell-derived IL-16 in atopic dermatitis. J Allergy Clin Immunol 109:681–687PubMedCrossRefGoogle Scholar
  98. 98.
    Hauk PJ, Leung DY (2001) Tacrolimus (FK506): new treatment approach in superantigen-associated diseases like atopic dermatitis? J Allergy Clin Immunol 107:391–392PubMedCrossRefGoogle Scholar
  99. 99.
    Wollenberg A, Sharma S, von BD, Geiger E, Haberstok J, Bieber T (2001) Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 107:519–525PubMedCrossRefGoogle Scholar
  100. 100.
    Novak N, Valenta R, Bohle B, Laffer S, Haberstok J, Kraft S, Bieber T (2004) FcepsilonRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J Allergy Clin Immunol 113:949–957PubMedCrossRefGoogle Scholar
  101. 101.
    Matsue H, Yang C, Matsue K, Edelbaum D, Mummert M, Takashima A (2002) Contrasting impacts of immunosuppressive agents (rapamycin, FK506, cyclosporin A, and dexamethasone) on bidirectional dendritic cell-T cell interaction during antigen presentation. J Immunol 169:3555–3564PubMedGoogle Scholar
  102. 102.
    Duperrier K, Velten FW, Bohlender J, Demory A, Metharom P, Goerdt S (2005) Immunosuppressive agents mediate reduced allostimulatory properties of myeloid-derived dendritic cells despite induction of divergent molecular phenotypes. Mol Immunol 42:1531–1540PubMedCrossRefGoogle Scholar
  103. 103.
    Panhans-Gross A, Novak N, Kraft S, Bieber T (2001) Human epidermal Langerhans' cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 107:345–352PubMedCrossRefGoogle Scholar
  104. 104.
    Stuetz A, Baumann K, Grassberger M, Wolff K, Meingassner JG (2006) Discovery of topical calcineurin inhibitors and pharmacological profile of pimecrolimus. Int Arch Allergy Immunol 141:199–212PubMedCrossRefGoogle Scholar
  105. 105.
    Krummen MB, Varga G, Steinert M, Stuetz A, Luger TA, Grabbe S (2006) Effect of pime-crolimus vs. corticosteroids on murine bone marrow-derived dendritic cell differentiation, maturation and function. Exp Dermatol 15:43–50Google Scholar
  106. 106.
    Szabo G, Gavala C, Mandrekar P (2001) Tacrolimus and cyclosporine A inhibit allostimula-tory capacity and cytokine production of human myeloid dendritic cells. J Investig Med 49:442–449PubMedCrossRefGoogle Scholar
  107. 107.
    Wada K, Kaminuma O, Mori A, Nakata A, Ogawa K, Kikkawa H, Ikezawa K, Suko M, Okudaira H (1998) IL-5-producing T cells that induce airway eosinophilia and hyperrespon-siveness are suppressed by dexamethasone and cyclosporin A in mice. Int Arch Allergy Immunol 117 Suppl 1:24–27CrossRefGoogle Scholar
  108. 108.
    Park CW, Lee BH, Han HJ, Lee CH, Ahn HK (2005) Tacrolimus decreases the expression of eotaxin, CCR3, RANTES and interleukin-5 in atopic dermatitis. Br J Dermatol 152:1173–1181PubMedCrossRefGoogle Scholar
  109. 109.
    Ito F, Toyota N, Sakai H, Takahashi H, Iizuka H (1999) FK506 and cyclosporin A inhibit stem cell factor-dependent cell proliferation/survival, while inducing upregulation of c-kit expression in cells of the mast cell line MC/9. Arch Dermatol Res 291:275–283PubMedCrossRefGoogle Scholar
  110. 110.
    Sengoku T, Kishi S, Sakuma S, Ohkubo Y, Goto T (2000) FK506 inhibition of histamine release and cytokine production by mast cells and basophils. Int J Immunopharmacol 22:189–201PubMedCrossRefGoogle Scholar
  111. 111.
    Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, Henz BM (2001) The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils. J Allergy Clin Immunol 108:275–280PubMedCrossRefGoogle Scholar
  112. 112.
    Lan CC, Kao YH, Huang SM, Yu HS, Chen GS (2004) FK506 independently upregulates transforming growth factor beta and downregulates inducible nitric oxide synthase in cultured human keratinocytes: possible mechanisms of how tacrolimus ointment interacts with atopic skin. Br J Dermatol 151:679–684PubMedCrossRefGoogle Scholar
  113. 113.
    Muschen A, Mirmohammadsadegh A, Jarzebska-Deussen B, Abts HF, Ruzicka T, Michel G (1999) Differential IL-10 receptor gene expression in acute versus chronic atopic eczema. Modulation by immunosuppressive drugs and cytokines in normal cultured keratinocytes. Inflamm Res 48:539–543PubMedCrossRefGoogle Scholar
  114. 114.
    Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, Schuler W, Schulz M, Werner FJ, Winiski A, Wolff B, Zenke G (1999) A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol 141:264–273PubMedCrossRefGoogle Scholar
  115. 115.
    Karashima T, Hachisuka H, Sasai Y (1996) FK506 and cyclosporin A inhibit growth factor-stimulated human keratinocyte proliferation by blocking cells in the G0/G1 phases of the cell cycle. J Dermatol Sci 12:246–254PubMedCrossRefGoogle Scholar
  116. 116.
    Grundmann-Kollmann M, Podda M, Ochsendorf F, Boehncke WE, Kaufmann R, Zollner TM (2001) Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 137:870–873PubMedGoogle Scholar
  117. 117.
    Heller M, Shin HR, Orlow SJ, Schaffer JV (2007) Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol 157:127–132PubMedCrossRefGoogle Scholar
  118. 118.
    Murray ML, Cohen JB (2007) Mycophenolate mofetil therapy for moderate to severe atopic dermatitis. Clin Exp Dermatol 32:23–27PubMedGoogle Scholar
  119. 119.
    Hantash B, Fiorentino D (2006) Liver enzyme abnormalities in patients with atopic dermatitis treated with mycophenolate mofetil. Arch Dermatol 142:109–110PubMedCrossRefGoogle Scholar
  120. 120.
    Hansen ER, Buus S, Deleuran M, Andersen KE (2000) Treatment of atopic dermatitis with mycophenolate mofetil. Br J Dermatol 143:1324–1326PubMedCrossRefGoogle Scholar
  121. 121.
    Goujon C, Berard F, Dahel K, Guillot I, Hennino A, Nosbaum A, Saad N, Nicolas JF (2006) Methotrexate for treatment of adult atopic dermatitis. Eur J Dermatol 16:155–158PubMedGoogle Scholar
  122. 122.
    Weatherhead SC, Wahie S, Reynolds NJ, Meggitt SJ (2007) An open-label, dose ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol 156:346–351PubMedCrossRefGoogle Scholar
  123. 123.
    Balasubramaniam P, Ilchyshyn A (2005) Successful treatment of severe atopic dermatitis with methotrexate. Clin Exp Dermatol 30:436–437PubMedCrossRefGoogle Scholar
  124. 124.
    Paul C, Lahfa M, Bachelez H, Chevret S, Dubertret L (2002) A randomized controlled evaluator-blinded trial of intravenous immunoglobulin in adults with severe atopic dermatitis. Br J Dermatol 147:518–522PubMedCrossRefGoogle Scholar
  125. 125.
    Jolles S, Sewell C, Webster D, Ryan A, Heelan B, Waite A, Rustin M (2003) Adjunctive high-dose intravenous immunoglobulin treatment for resistant atopic dermatitis: efficacy and effects on intracellular cytokine levels and CD4 counts. Acta Derm Venerol 83:433–437PubMedCrossRefGoogle Scholar
  126. 126.
    Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, Chevailler A, Mouthon L, Weill B, Bruneval P, Kazatchkine MD, Kaveri SV (2003) Inhitibion of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101:758–765PubMedCrossRefGoogle Scholar
  127. 127.
    Bayry L, Lacroix-Desmazes S, Delignat S, Mouthon L, Weill B, Kazatchkine MD, Kaveri SV (2003) Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon-alpha present in serum from patients with systemic lupus erythematosus. Arthritis Rheum 48:3497–4502PubMedCrossRefGoogle Scholar
  128. 128.
    Samuelsson A, Towers TL, Ravetch JV (2001) Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484–486PubMedCrossRefGoogle Scholar
  129. 129.
    Altznauer F, von Gunten S, Spath P, Simon HU (2003) Concurrent presence of agonistic and antagonistic anti-CD95 autoantibodies in intravenous Ig preparations. J Allergy Clin Immunol 112:1185–1190PubMedCrossRefGoogle Scholar
  130. 130.
    Andersson J, Skansen-Saphir U, Sparrelid E, Andersson U (1996) Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. Clin Exp Immunol 104:10–20PubMedGoogle Scholar
  131. 131.
    Spahnn JD, Leung DY, Chan MT, Szefler SJ, Gelfand EW (1999) Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunoglobulin. J Allergy Clin Immunol 103:421–426CrossRefGoogle Scholar
  132. 132.
    Wilsmann-Theis D, Martin S, Reber M, Kwiek B, Bieber T, Novak N (2006) Biologicals dramatic advances in the treatment of psoriasis. Curr Pharm Des 12:989–999PubMedCrossRefGoogle Scholar
  133. 133.
    Leonardi CL (2003) Efalizumab: an overview. J Am Acad Dermatol 49:S98–S104PubMedCrossRefGoogle Scholar
  134. 134.
    Takiguchi R, Tofte S, Simpson B, Harper E, Blauvelt A, Hanifin J, Simpson E (2007) Efalizumab for severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol 56:222–227PubMedCrossRefGoogle Scholar
  135. 135.
    Weinberg JM, Siegfried EC (2006) Successful treatment of severe atopic dermatitis in a child and an adult with the T-cell modulator efalizumab. Arch Dermatol 142:555–558PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Bartlomiej Kwiek
    • 1
  • Natalija Novak
    • 2
  1. 1.Department of DermatologyMedical University of WarsawWarsawPoland
  2. 2.Department of Dermatology and AllergyUniversity of BonnBonnGermany

Personalised recommendations