Publikationsserver der Universitätsbibliothek Marburg

Titel:Investigating the efficacy of transcription factor-specific DNAzymes in animal models of inflammatory skin diseases
Autor:Ibrahim, Rouba
Weitere Beteiligte: Garn, Holger (PD Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0207
URN: urn:nbn:de:hebis:04-z2016-02077
DOI: https://doi.org/10.17192/z2016.0207
DDC: Medizin
Titel (trans.):Untersuchungen zur Wirksamkeit Transkriptionsfaktor-spezifischer DNAzyme in Tiermodellen für entzündliche Hauterkrankungen
Publikationsdatum:2016-04-14
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Tbet, Oxazolon, Skin inflammation, GATA3, Tbet, GATA3, DNAzyme, Entzündliche Hauterkrankungen, oxazolone, DNAzyme

Summary:
Inflammatory skin diseases cover a wide range of skin conditions that cause dry, itchy, scaly skin and affects millions around the world. Current therapies are mostly symptomatic and often associated with a wide range of side effects. Therefore, there is a growing need for a more specific therapy targeting key molecules in the pathogenesis of such diseases. Investigations revealed a central role for different T helper subsets in the immunopathology of these skin diseases. Atopic dermatitis (Th2), contact dermatitis (Th1) and Psoriasis (Th1, Th17), are associated with one or more of these Th-phenotypes. The differentiation and activation of T helper subtypes is regulated by different transcription factors. This study focused on two specific transcription factors GATA3 and Tbet, which regulate the differentiation and activation of Th2 and Th1, respectively. The levels of these transcription factors were found to be elevated in diseases with the respective Th phenotype, which made them interesting targets for DNAzyme-based therapy. In order to test the efficacy of such transcription factor-specific DNAzymes, two different animal models of inflammatory allergic skin diseases were established. In the first model skin injury and the hapten oxazolone were used to elicit a Th2-dominant contact hypersensitivity with features similar to those of atopic dermatitis. In the second model, Ovalbumin was used to induce a Th1-dominated inflammation in OVA-specific T cell receptor- transgenic mice after systemic sensitization with OVA/CFA. Effects of topical preventive treatment with GATA3-specific DNAzyme (hgd40) were investigated in the oxazolone model. The DNAzymes were formulated in w/o/w emulsion for protection against degradation and an enhanced skin penetration. Compared to placebo and control non-specific DNAzyme ODNg3, prophylactic treatment with hgd40 significantly reduced skin swelling. It also resulted in lower numbers of CD4+ cells infiltrating the dermis. This was associated with a downregulation of GATA3 mRNA expression in the skin early in the sensitization phase. Similar reduction in skin swelling was also observed after a semi-therapeutic treatment, in which hgd40 was first applied 24 h prior to challenge but not during sensitization. Using the OVA/CFA model, effects of the Tbet-specific DNAzyme td32 treatment were evaluated. Data indicated a significant reduction in skin swelling following prophylactic treatment with emulsions containing td32. No such effect was observed in the control DNAzyme ODNg3 or placebo groups. In addition, no influence on the progression of skin swelling in this Th1-skewed skin inflammation after treatment with hgd40 was detected, which further supports the hypothesis of specific targeting of Tbet. In summary, this study shows that treatment with DNAzymes, targeting Th1- and Th2- specific transcription factors Tbet and GATA3 improved inflammatory symptoms in vivo. These results pose the DNAzyme as promising tools for future topical treatment of inflammatory skin diseases.

Bibliographie / References

  1. Silverman SK (2005): In vitro selection, characterization, and application of deoxyribozymes that cleave RNA. In Nucleic Acids Res. 33 (19), pp. 6151–6163.
  2. Rácz E, Kurek D, Kant M, Baerveldt EM, Florencia E, Mourits S et al. (2011): GATA3 Expression Is Decreased in Psoriasis and during Epidermal Regeneration; Induction by Narrow-Band UVB and IL-4. In PLoS One 6 (5), pp. e19806.
  3. Larsen FS, Hanifin JM. (2002): Epidemiology of atopic dermatitis. In Immunol Allergy Clin North Am 22 (1), pp. 1–24.
  4. Schmidts T, Marquardt K, Schlupp P, Dobler D, Heinz F, Mäder U et al. (2012): Development of drug delivery systems for the dermal application of therapeutic DNAzymes. In Int J Pharm. 431 (1–2), pp. 61–69. DOI: 10.1016/j.ijpharm.2012.04.034.
  5. Peiser M, Tralau T, Heidler J, Api AM, Arts JHE, Basketter DA et al. (2012): Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. In: Cell. Mol. Life Sci. 69 (5), pp. 763–781.
  6. Schubert S (2003): RNA cleaving '10-23' DNAzymes with enhanced stability and activity. In Nucleic Acids Res. 31 (20), pp. 5982–5992.
  7. Mitchell A, Dass CR, Sun LQ, Khachigian LM (2004): Inhibition of human breast carcinoma proliferation, migration, chemoinvasion and solid tumour growth by DNAzymes targeting the zinc finger transcription factor EGR-1. In Nucleic Acids Res 32 (10), pp. 3065–3069.
  8. Kaufman CK, Zhou P, Pasolli HA, Rendl M, Bolotin D, Lim KC et al. (2003): GATA-3: an unexpected regulator of cell lineage determination in skin. In Genes Dev 17 (17), pp. 2108–2122.
  9. Grice EA, Kong HH, Renaud G, Young AC, Bouffard GG, Blakesley RW et al. (2008): A diversity profile of the human skin microbiota. In Genome Res 18 (7), pp. 1043–1050.
  10. Huebner M, Kim DY, Ewart S, Karmaus W, Sadeghnejad A, Arshad SH: Patterns of GATA3 and IL13 gene polymorphisms associated with childhood rhinitis and atopy in a birth cohort. In J Allergy Clin Immunol 121 (2), pp. 408–414.
  11. Arshad SH, Karmaus W, Kurukulaaratchy R, Sadeghnejad A, Huebner M, Ewart S (2008): Polymorphisms in the interleukin 13 and GATA binding protein 3 genes and the development of eczema during childhood. In Br J Dermatol 158 (6), pp. 1315–1322.
  12. Black, APB, Ardern-Jones MR, Kasprowicz V, BownessP, Jones L, Bailey AS, Ogg GS (2007): Human keratinocyte induction of rapid effector function in antigen-specific memory CD4+ and CD8+ T cells. In Eur. J. Immunol. 37 (6), pp. 1485–1493.
  13. Shklovskaya E, O'Sullivan BJ, Ng LG, Roediger B, Thomas R, Weninger W, Fazekas de St Groth B (2011): Langerhans cells are precommitted to immune tolerance induction. In Proc Nat Acad Sci. 108 (44), pp. 18049–18054.
  14. LNAzymes: Incorporation of LNA-Type Monomers into DNAzymes Markedly Increases RNA Cleavage. In J. Am. Chem. Soc. 124 (46), pp. 13682–13683.
  15. Liberman AC, Druker J, Refojo D, Holsboer F, Arzt E (2009): Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells. In FASEB J 23 (5), pp. 1558–1571.
  16. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. In N Engl J Med. 372 (21), pp. 1987–1995.
  17. Cai H, Santiago FS, Prado-Lourenco L, Wang B, Patrikakis M, Davenport MP et al. (2012): DNAzyme Targeting c-jun Suppresses Skin Cancer Growth. In Sci Transl Med. 4 (139), pp. 139ra82.
  18. Chikh A, Sayan E, Thibaut S, Lena AM, DiGiorgi S, Bernard BA et al. (2007): Expression of GATA-3 in epidermis and hair follicle: Relationship to p63. In Biochem. Biophys. Res. Commun. 361 (1), pp. 1–6.
  19. McAleer MA, Irvine AD (2013): The multifunctional role of filaggrin in allergic skin disease. In J Allergy Clin Immunol 131 (2), pp. 280–291.
  20. Kanhere A, Hertweck A, Bhatia U, Gökmen MR, Perucha E, Jackson I et al. (2012): T- bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. In Nat Commun 3, p. 1268.
  21. Dicke T, Pali-Schöll I, Kaufmann A, Bauer S, Renz H, Garn H (2012): Absence of Unspecific Innate Immune Cell Activation by GATA-3-Specific DNAzymes. In Nucleic Acid Ther 22 (2), pp. 117–126.
  22. Activation of the IL-1[beta]-Processing Inflammasome Is Involved in Contact Hypersensitivity. In J Invest Dermatol 127 (8), pp. 1956–1963.
  23. Breaker, R. R.; Joyce, G. F. (1994): A DNA enzyme that cleaves RNA. In Chem Biol 1 (4), pp. 223–229.
  24. Breaker R R, Joyce GF (1995): A DNA enzyme with Mg (2+)-dependent RNA phosphoesterase activity. In Chem Biol 2 (10), pp. 655–660.
  25. Fonacier LS, Dreskin SC, Leung DYM (2010): Allergic skin diseases. In J Allergy Clin Immunol 125 (2), pp. S138.
  26. Ghoreschi K, Mrowietz U, Röcken M (2003): A molecule solves psoriasis? Systemic therapies for psoriasis inducing interleukin 4 and Th2 responses. In J Mol Med (Berl) 81 (8), pp. 471–480.
  27. Zhang P, Chen HX, Duan YQ, Wang WZ, Zhang TZ, Li JW, Tu YT (2014): Analysis of Th1/Th2 response pattern for erythrodermic psoriasis. In J Huazhong Univ Sci and Technolog Med Sci. 34 (4), pp. 596–601.
  28. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. In N Engl J Med. 366 (13), pp. 1181–1189.
  29. Zollner T, Renz H, Asadullah K (2004): Animal models of T cell-mediated skin diseases. 1 st ed. Berlin, New York: Springer-Verlag Berlin Heidelberg (Ernst Schering Research Foundation workshop, 50).
  30. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. In N Engl J Med. 366 (13), pp. 1190–1199.
  31. Turowska A, Librizzi D, Baumgartl N, Kuhlmann J, Dicke T, Merkel O et al. (2013): Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs. In Toxicol Appl Pharmacol 272 (2), pp. 365–372.
  32. Dass CR, Saravolac EG, Li Y Sun LQ (2002): Cellular uptake, distribution, and stability of 10-23 deoxyribozymes. In Antisense Nucleic Acid Drug Dev 12 (5), pp. 289–299..
  33. Romani N, Brunner PM, Stingl G (2012): Changing Views of the Role of Langerhans Cells. In J Invest Dermatol 132 (3), pp. 872–881.
  34. Zhang L, Tinkle SS (2000): Chemical Activation of Innate and Specific Immunity in Contact Dermatitis. In J Invest Dermatol 115 (2), pp. 168–176.
  35. Homey B, Steinhoff M, RuzickaT, Leung DYM (2006): Cytokines and chemokines orchestrate atopic skin inflammation. In J Allergy Clin Immunol 118 (1), pp. 178–189.
  36. Khachigian LM (2004): Deoxyribozymes as inhibitors of vascular smooth muscle cell growth. In Curr pharm biotechnol. 5 (4), pp. 337–339.
  37. Emilsson GM, Breaker RR (2002): Deoxyribozymes: new activities and new applications. In Cell Mol Life Sci 59 (4), pp. 596–607.
  38. Pierre P, Turley SJ, Gatti E, Hull M, Meltzer J, Mirza A et al. (1997): Developmental regulation of MHC class II transport in mouse dendritic cells. In Nature 388 (6644), pp. 787–792.
  39. Schmidts T, Marquardt K, Schlupp P, Dobler D, Heinz F, Mader U et al. (2012): Development of drug delivery systems for the dermal application of therapeutic DNAzymes. In Int J Pharm.
  40. Dupilumab Treatment in Adults with Moderate-to-Severe Atopic Dermatitis. In N Engl J Med 371 (2), pp. 130–139.
  41. Kaplan DH, Igyártó BZ, Gaspari AA (2012): Early immune events in the induction of allergic contact dermatitis. In Nat Rev Immunol.
  42. Sel S, Wegmann M, Dicke T, Sel S, Henke W, Yildirim AÖ et al. (2008): Effective prevention and therapy of experimental allergic asthma using a GATA-3–specific DNAzyme. In J Allergy Clin Immunol. 121 (4), pp. 910–916.e5.
  43. Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME, Fisher J, Hussain I (2006): Efficacy of anti-IgE therapy in patients with atopic dermatitis. In J Am Acad Dermatol. 55 (1), pp. 168–170..
  44. Ulrich Purath*, Rouba Ibrahim*, Jana Zeitvogel, Harald Renz, Frank Runkel, Thomas Schmidts, Dorota Dobler, Thomas Werfel, Anke Müller, Holger Garn. Efficacy of T cell transcription factor-specific DNAzymes in murine skin inflammation models. J Allergy Clin Immunol (Paper accepted).
  45. Matsumoto K, Mizukoshi K, Oyobikawa M, Ohshima H, Tagami H (2004): Establishment of an atopic dermatitis-like skin model in a hairless mouse by repeated elicitation of contact hypersensitivity that enables to conduct functional analyses of the stratum corneum with various non-invasive biophysical instruments. In Skin Res Technol 10 (2), pp. 122–129.
  46. Kusumoto M, Xu B, Shi M, Matsuyama T, Aoyama K, Takeuchi T (2007): Expression of chemokine receptor CCR4 and its ligands (CCL17 and CCL22) in murine contact hypersensitivity. In J Interferon Cytokine Res 27 (11), pp. 901–910.
  47. Zhu K, Ye J, Wu M, Cheng H (2010): Expression of Th1 and Th2 cytokine-associated transcription factors, T-bet and GATA-3, in peripheral blood mononuclear cells and skin lesions of patients with psoriasis vulgaris. In Arch Dermatol Res 302 (7), pp. 517–523.
  48. Krathen RA, Hsu S (2005): Failure of omalizumab for treatment of severe adult atopic dermatitis. In J Am Acad Dermatol 53 (2), pp. 338–340.
  49. Zhu J, Yamane H, Cote-Sierra J, Guo L, Paul WE (2006): GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. In Cell Res 16 (1), pp. 3–10.
  50. Schoepe S, Schäcke H, May E, Asadullah K (2006): Glucocorticoid therapy-induced skin atrophy. In Exp Dermatol. 15 (6), pp. 406–420.
  51. Zhu J, Guo L, Min B, Watson CJ, Hu-Li J, Young HA et al. (2002): Growth Factor Independent-1 Induced by IL-4 Regulates Th2 Cell Proliferation. In Immunity 16 (5), pp. 733–744.
  52. Divkovic M, Pease CK, Gerberick GF, Basketter DA (2005): Hapten–protein binding: from theory to practical application in the in vitro prediction of skin sensitization. In Contact Dermatitis 53 (4), pp. 189–200.
  53. Lebre MC, van der Aar AM, van Baarsen L, van Capel TM, Schuitemaker JH, Kapsenberg ML, de Jong EC (2006): Human Keratinocytes Express Functional Toll-Like Receptor 3, 4, 5, and 9. In J Investig Dermatol 127 (2), pp. 331–341.
  54. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007): IL-17 family cytokines and the expanding diversity of effector T cell lineages. In Annu Rev Immunol 25, pp. 821– 852.
  55. Christensen AD, Haase C (2012): Immunological mechanisms of contact hypersensitivity in mice. In APMIS 120 (1), pp. 1–27.
  56. Kupper TS (2003): Immunologic Targets in Psoriasis. In N Engl J Med 349 (21), pp. 1987–1990.
  57. Hultsch T, Kapp A, Spergel J (2005): Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. In Dermatology 211 (2), pp. 174–187.
  58. Martins LE, Reis VM (2011): Immunopathology of allergic contact dermatitis. In An. Bras. Dermatol 86 (3), pp. 419–433.
  59. Fiset PO, Leung DYM, Hamid Q (2006): Immunopathology of atopic dermatitis. In J Allergy Clin Immunol 118 (1), pp. 287–290.
  60. Aioi A, Tonogaito H, Suto H, Hamada K, Ra C, Ogawa H. et al. (2001): Impairment of skin barrier function in NC/Nga Tnd mice as a possible model for atopic dermatitis. In Br J Dermatol 144 (1), pp. 12–18
  61. Shibaki A, Katz SI (2002): Induction of skewed Th1/Th2 T-cell differentiation via subcutaneous immunization with Freund's adjuvant. In Exp Dermatol 11 (2), pp. 126– 134.
  62. Oren A, Ganz T, Liu L, Meerloo T (2003): In human epidermis, β-defensin 2 is packaged in lamellar bodies. In Exp Mol Pathol 74 (2), pp. 180–182.
  63. Schuller E, Teichmann B, Haberstok J, Moderer M, Bieber T, Wollenberg A (2001): In situ expression of the costimulatory molecules CD80 and CD86 on Langerhans cells and inflammatory dendritic epidermal cells (IDEC) in atopic dermatitis. In Arch Dermatol Res. 293 (9), pp. 448–454.
  64. Hornung V, Latz E (2010): Intracellular DNA recognition. In Nat Rev Immunol 10 (2), pp. 123–130.
  65. Webb EF, Tzimas MN, Newsholme SJ, Griswold DE (1998): Intralesional Cytokines in Chronic Oxazolone-Induced Contact Sensitivity Suggest Roles for Tumor Necrosis Factor α and Interleukin-4. In J Investig Dermatol 111 (1), pp. 86–92.
  66. Albanesi C, Scarponi C, Giustizieri ML, Girolomoni G (2005): Keratinocytes in Inflammatory Skin Diseases. In Curr Drug targets inflamm allergy 4 (3), pp. 329–334.
  67. Braff MH, Di Nardo A, Gallo RL (2005): Keratinocytes Store the Antimicrobial Peptide Cathelicidin in Lamellar Bodies. In J Investig Dermatol 124 (2), pp. 394–400.
  68. Langerhans Cells Favor Skin Flora Tolerance through Limited Presentation of Bacterial Antigens and Induction of Regulatory T Cells. In J Investig Dermatol 133 (5), pp. 1240– 1249.
  69. Oyoshi MK, Larson RP, Ziegler SF, Geha RS (2010): Mechanical injury polarizes skin dendritic cells to elicit a TH2 response by inducing cutaneous thymic stromal lymphopoietin expression. In J Allergy Clin Immunol 126 (5), pp. 976–984.e5.
  70. Santoro SW, Joyce GF (1998): Mechanism and utility of an RNA-cleaving DNA enzyme. In Biochemistry 37 (38), pp. 13330–13342.
  71. Schäcke H, Döcke WD, Asadullah K (2002): Mechanisms involved in the side effects of glucocorticoids. In Pharmacol Ther. 96 (1), pp. 23–43.
  72. Martin SF, Esser PR, Weber FC, Jakob T, Freudenberg MA, Schmidt M, Goebeler M (2011): Mechanisms of chemical-induced innate immunity in allergic contact dermatitis. In Allergy 66 (9), pp. 1152–1163.
  73. Vähävihu K, Ala-Houhala M, Peric M, Karisola P, Kautiainen H, Hasan T et al. (2010): Narrowband ultraviolet B treatment improves vitamin D balance and alters antimicrobial peptide expression in skin lesions of psoriasis and atopic dermatitis. In Br J Dermatol 163 (2), pp. 321–328.
  74. Lambers H, Piessens S, Bloem A, Pronk H, Finkel P (2006): Natural skin surface pH is on average below 5, which is beneficial for its resident flora. In Int J Cosmet Sci 28 (5), pp. 359–370.
  75. Merad M, Ginhoux F, Collin M (2008): Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. In Nat Rev Immunol 8 (12), pp. 935– 947.
  76. Kondo H, Ichikawa Y, Imokawa G (1998): Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response. In Eur J Immunol 28 (3), pp. 769–779.
  77. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. In J clin oncol. 23 (18), pp. 4089–4099.
  78. Cho SH, Strickland I, Tomkinson A, Fehringer AP, Gelfand EW, Leung DYM (2001): Preferential Binding of Staphylococcus aureus to Skin Sites of Th2-Mediated Inflammation in a Murine Model. In J Investig Dermatol 116 (5), pp. 658–663.
  79. Schmidts T, Dobler D, von den Hoff S, Schlupp P, Garn H, Runkel F (2011): Protective effect of drug delivery systems against the enzymatic degradation of dermally applied DNAzyme. In Int J Pharm. 410 (1-2), pp. 75–82.
  80. Weiss DL, Brown MA (2001): Regulation of IL-4 production in mast cells: a paradigm for cell-type-specific gene expression. In Immunol Rev 179 (1), pp. 35–47.
  81. Homburg U, Renz H, Timmer W, Hohlfeld JM, Seitz F, Lüer K et al.: Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma. In J Allergy Clin Immunol.
  82. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. In Br J Dermatol. 168 (2), pp. 402–411.
  83. Yoo J (2005): Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. In J Exp Med 202 (4), pp. 541– 549.
  84. Lazarevic V, Glimcher LH, Lord GM (2013): T-bet: a bridge between innate and adaptive immunity. In Nat Rev Immunol 13 (11), pp. 777–789.
  85. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY et al. (2002): T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. In Nat Immunol 3 (6), pp. 549–557.
  86. Kuo IH, Yoshida T, De Benedetto A, Beck LA (2013): The cutaneous innate immune response in patients with atopic dermatitis. In J Allergy Clin Immunol 131 (2), pp. 266– 278.
  87. Thyssen JP, Linneberg A, Menné T, Johansen JD (2007): The epidemiology of contact allergy in the general population – prevalence and main findings. In Contact Dermatitis 57 (5), pp. 287–299.
  88. Mjösberg J, Bernink J, Golebski K, Karrich JJ, Peters CP, Blom B et al. (2012): The Transcription Factor 5GATA36 Is Essential for the Function of Human Type 2 Innate Lymphoid Cells. In Immunity 37 (4), pp. 649–659.
  89. He R, Geha RS (2010): Thymic stromal lymphopoietin. In Annals of the New York Academy of Sciences 1183, pp. 13–24.
  90. Steinman RM, Hawiger D, Nussenzweig MC (2003): Tolerogenic dendritic cells. In Annu. Rev. Immunol. 21 (1), pp. 685–711.
  91. Fuhst R, Runge F, Buschmann J, Ernst H, Praechter C, Hansen T et al. (2012): Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure. In Pulm.Pharmacol Ther. 26 (2), pp.281-289.
  92. Holgate ST, Polosa R (2008): Treatment strategies for allergy and asthma. In Nat Rev Immunol 8 (3), pp. 218–230.
  93. Walling HW, Swick BL (2010): Update on the management of chronic eczema: new approaches and emerging treatment options. In Clin Cosmet Investig Dermato (3), pp. 99–117.
  94. Van der Aar AM, Sibiryak DS, Bakdash G, van Capel TM, van der Kleij HP, Opstelten DJ et al. (2011): Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells. In J Allergy Clin Immunol 127 (6), pp. 1532–1540.e7.
  95. Odell ID, Cook D (2013): Immunofluorescence Techniques. In J Investig Dermatol 133 (1), pp. e4.
  96. Ibrahim R, Purath U, Turowska A, Homburg U, Runkel F, Schmidts T, Dobler D; Renz H, Garn H; Mueller A " Effects of interference with GATA-3 expression by target-specific DNAzyme treatment on disease progression in a subacute oxazolone-induced mouse model of atopic dermatitis " Clin Transl Allergy. 2015; 5 (Suppl 1): O21.
  97. Kimber I, Dearman RJ (2002): Allergic contact dermatitis: the cellular effectors. In Contact Dermatitis 46 (1), pp. 1–5.
  98. Thomson JA, Troutt AB, Kelso A (1993): Contact sensitization to oxazolone: involvement of both interferon-gamma and interleukin-4 in oxazolone-specific Ig and T-cell responses. In Immunology 78 (2), pp. 185–192.
  99. Dearman RJ, Ramdin LS, Basketter DA, Kimber I (1994): Inducible interleukin-4- secreting cells provoked in mice during chemical sensitization. In Immunology 81 (4), pp. 551–557.
  100. Arakawa S, Hatano Y, Katagiri K (2004): Differential expression of mRNA for Th1 and Th2 cytokine-associated transcription factors and suppressors of cytokine signaling in peripheral blood mononuclear cells of patients with atopic dermatitis. In Clin Exp Immunol 135 (3), pp. 505–510.
  101. Guzman Strong C, Wertz PW, Wang C, Yang F, Meltzer PS, Andl T et al. (2006): Lipid defect underlies selective skin barrier impairment of an epidermal-specific deletion of Gata-3. In J Cell Biol 175 (4), pp. 661–670.
  102. Santoro SW, Joyce GF (1997): A general purpose RNA-cleaving DNA enzyme. In Proc Natl Acad Sci U S A 94 (9), pp. 4262–4266.
  103. Wagner H, Bauer S (2006): All is not Toll: new pathways in DNA recognition. In J Exp Med 203 (2), pp. 265–268.
  104. Yamane H, Zhu J, Paul WE (2005): Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. In J Exp Med 202 (6), pp. 793–804.
  105. Man MQ, Hatano Y, Lee SH, Man M, Chang S, Feingold KR et al. (2007): Characterization of a Hapten-Induced, Murine Model with Multiple Features of Atopic Dermatitis: Structural, Immunologic, and Biochemical Changes following Single Versus Multiple Oxazolone Challenges. In J Investig Dermatol 128 (1), pp. 79–86.
  106. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T et al. (2009): IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. In J Allergy Clin Immunol 123 (6), pp. 1244-1252.e2.
  107. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ (2009): Skin immune sentinels in health and disease. In Nat Rev Immunol.
  108. Wei G, Abraham BJ, Yagi R, Jothi R, Cui K, Sharma S et al. (2011): Genome-wide Analyses of Transcription Factor GATA3-Mediated Gene Regulation in Distinct T Cell Types. In Immunity 35 (2), pp. 299–311.
  109. Kubo A, Nagao K, Amagai M (2012): Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. In J. Clin. Invest. 122 (2), pp. 440–447.
  110. Oyoshi MK, He Rui, Li Y, Mondal S, Yoon J, Afshar R et al. (2012): Leukotriene B4- Driven Neutrophil Recruitment to the Skin Is Essential for Allergic Skin Inflammation. In Immunity 37 (4), pp. 747–758.
  111. Kim BS, Siracusa MC, Saenz SA, Noti, M, Monticelli LA, Sonnenberg GF et al. (2013): TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. In Sci Transl Med 5 (170), pp. 170ra16.
  112. The Transcription Factor GATA-3 Controls Cell Fate and Maintenance of Type 2 Innate Lymphoid Cells. In Immunity 37 (4), pp. 634–648.
  113. Spergel JM, Mizoguchi E, Oettgen H, Bhan AK, Geha RS (1999): Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. In J Clin Invest. 103 (8), pp. 1103– 1111.
  114. Godfrey DI, Kronenberg M (2004): Going both ways: Immune regulation via CD1d- dependent NKT cells. In J Clin Invest 114 (10), pp. 1379–1388.
  115. Muehleisen B et al (2013): Vitamin D in allergic disease: Shedding light on a complex problem. In J Allergy Clin Immunol 131 (2), pp. 324–329.
  116. Tindemans I, Serafini N, Di Santo JP, Hendriks RW (2014): GATA-3 Function in Innate and Adaptive Immunity. In Immunity 41 (2), pp. 191–206.


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