Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD. Methods:
This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2-4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays. Results:
All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group. Conclusions:
Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L.
- Berger W, Gupta N, McAlary M, Fowler-Taylor A: Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma. Ann Allergy Asthma Immunol 2003;91:182-188.
- MacGlashan DW Jr, Bochner BS, Adelman DC, Jardieu PM, Togias A, McKenzie-White J, Sterbinsky SA, Hamilton RG, Lichtenstein LM: Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody. J Immunol 1997;158:1438-1445.
- Prussin C, Griffith DT, Boesel KM, Lin H, Foster B, Casale TB: Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol 2003;112:1147-1154.
- Kemp AS: Atopic eczema: Its social and financial costs. J Paediatr Child Health 1999;35:229-231.
- Hirata T, Furie BC, Furie B: P-, e-, and l-selectin mediate migration of activated CD8+ T lymphocytes into inflamed skin. J Immunol 2002;169:4307-4313.
- Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt Rd R, Bazan F, Kastelein RA, Liu YJ: Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673-680.
- Corrigan CJ, Jayaratnam A, Wang Y, Liu Y, de Waal Malefyt R, Meng Q, Kay AB, Phipps S, Lee TH, Ying S: Early production of thymic stromal lymphopoietin precedes infiltration of dendritic cells expressing its receptor in allergen-induced late-phase cutaneous responses in atopic subjects. Allergy 2009;64:1014-1022.
- Liu YJ, Soumelis V, Watanabe N, Ito T, Wang YH, Malefyt ReW, Omori M, Zhou B, Ziegler SF: TSLP: An epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol 2007;25:193-219.
- Sismanopoulos N, Delivanis DA, Alysandratos KD, Angelidou A, Vasiadi M, Therianou A, Theoharides TC: IL-9 induces VEGF secretion from human mast cells and IL-9/IL-9 receptor genes are overexpressed in atopic dermatitis. PLoS One 2012;7:e33271.
- Belloni B, Ziai M, Lim A, Lemercier B, Sbornik M, Weidinger S, Andres C, Schnopp C, Ring J, Hein R, Ollert M, Mempel M: Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol 2007;120:1223-1225.
- Velling P, Skowasch D, Pabst S, Jansen E, Tuleta I, Grohé C: Improvement of quality of life in patients with concomitant allergic asthma and atopic dermatitis: one year follow-up of omalizumab therapy. Eur J Med Res 2011;16:407-410.
- Hamilton RG, Marcotte GV, Saini SS: Immunological methods for quantifying free and total serum IgE levels in allergy patients receiving omalizumab (Xolair) therapy. J Immunol Methods 2005;303:81-91.
- Severity scoring of atopic dermatitis: The SCORAD index. Consensus report of the European Task Force on atopic dermatitis. Dermatology 1993;186:23-31.
- Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N: Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells. J Allergy Clin Immunol 2007;119:982-990.
- Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H, Torii H, Asahina A, Onai N, Matsushima K, Tamaki K: Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity. J Allergy Clin Immunol 2001;107:535-541.
- Holgate S, Smith N, Massanari M, Jimenez P: Effects of omalizumab on markers of inflammation in patients with allergic asthma. Allergy 2009;64:1728-1736.
- Schroeder JT, Bieneman AP, Chichester KL, Hamilton RG, Xiao H, Saini SS, Liu MC: Decreases in human dendritic cell-dependent T(h)2-like responses after acute in vivo IgE neutralization. J Allergy Clin Immunol 2010;125:896-901.e896.
- Bedoret D, Singh AK, Shaw V, Hoyte EG, Hamilton R, Dekruyff RH, Schneider LC, Nadeau KC, Umetsu DT: Changes in antigen-specific T-cell number and function during oral desensitization in cow's milk allergy enabled with omalizumab. Mucosal Immunol 2012;5:267-276.
- Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, Hiegel A, Kamilaris J, Carlisle S, Yue X, Kulis M, Pons L, Vickery B, Burks AW: A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol 2011;127:654-660.
- Liu YJ: Thymic stromal lymphopoietin: Master switch for allergic inflammation. J Exp Med 2006;203:269-273.
- Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, Comeau MR, Campbell DJ, Ziegler SF: Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 2005;202:541-549.
- Seshasayee D, Lee WP, Zhou M, Shu J, Suto E, Zhang J, Diehl L, Austin CD, Meng YG, Tan M, Bullens SL, Seeber S, Fuentes ME, Labrijn AF, Graus YM, Miller LA, Schelegle ES, Hyde DM, Wu LC, Hymowitz SG, Martin F: In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin-driven atopic inflammation. J Clin Invest 2007;117:3868-3878.
- Barrios JL, Paradis L, Desroches A: Efficacy of omalizumab therapy in a case of severe atopic dermatitis. Allergy Asthma Clin Immunol 2011;7(suppl 2):A33.
Correspondence to: Dr. Shuba Rajashri Iyengar
Division of Pediatric Allergy and Immunology
Massachusetts General Hospital for Children
175 Cambridge Street, Suite 559a, Charles River Park South, Boston, MA 02114 (USA)
Received: November 19, 2012
Accepted after revision: March 1, 2013
Published online: June 27, 2013
Number of Print Pages : 5
Number of Figures : 0, Number of Tables : 1, Number of References : 23
International Archives of Allergy and Immunology
Vol. 162, No. 1, Year 2013 (Cover Date: August 2013)
Journal Editor: Valenta R. (Vienna), Bohle B. (Vienna)
ISSN: 1018-2438 (Print), eISSN: 1423-0097 (Online)
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