Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Khattri, Saakshi¹  Shemer, Avner³  Rozenblit, Mariya^1,2,4  Dhingra, Nikhil^1,5  Czarnowicki, Tali^1,2  Finney, Robert^1,6  Gilleaudeau, Patricia¹  Sullivan-Whalen, Mary¹  Zheng, Xiuzhong¹  Xu, Hui¹  Cardinale, Irma¹  Strong, Cristina de Guzman⁷  Gonzalez, Juana¹  Suarez-Farinas, Mayte^1,2  Krueger, Jim G.^1,2  Guttman-Yassky, Emma^1,4 

[1] Rockefeller Univ, Lab Invest Dermatol, New York, NY 10065 USA

[2] Rockefeller Univ, Ctr Clin & Translat Sci, New York, NY USA

[3] Dept Dermatol, Tel Aviv, Israel

[4] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY USA

[5] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA

[6] Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol, Philadelphia, PA 19107 USA

[7] Washington Univ, Sch Med, Dept Internal Med, Div Dermatol,Ctr Pharmacogen, St Louis, MO 63130 USA

关键词: Atopic dermatitis;    cyclosporine;    T cell;    immune;    epidermal abnormalities;    S100 proteins;   

DOI  :  10.1016/j.jaci.2014.03.003

来源: Elsevier

【 摘 要 】

Background: Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to T(H)2/T(H)22 cytokine activation. However, these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. Objective: We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. Methods: CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. Results: After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of T(H)2-, T(H)22-, and some T(H)17-related molecules (ie, IL-13, IL-22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. Conclusions: This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology.

【 授权许可】

Free