IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:130

Article

Krueger, James G.¹  Fretzin, Scott²  Suarez-Farinas, Mayte¹  Haslett, Patrick A.³  Phipps, Krista M.³  Cameron, Gregory S.³  McColm, Juliet⁴  Katcherian, Artemis¹  Cueto, Inna¹  White, Traci¹  Banerjee, Subhashis³  Hoffman, Robert W.³ 

[1] Rockefeller Univ, New York, NY 10065 USA

[2] Dawes Fretzin Dermatol Grp, Indianapolis, IN USA

[3] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[4] Eli Lilly & Co, Erl Wood, Surrey, England

关键词: Psoriasis;    IL-17;    T(H)17 cells;    TNF;   

DOI  :  10.1016/j.jaci.2012.04.024

来源: Elsevier

【 摘 要 】

Background: In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell-derived cytokines. Evidence suggests that the T(H)17 cell cytokine IL-17A (IL-17) might play a role in disease pathogenesis. Objective: We sought to understand the effect that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects. Methods: We examined skin lesions obtained from 40 subjects participating in a phase I, randomized, double-blind, placebo-controlled trial of the anti-IL-17 mAb ixekizumab (previouslyLY2439821) in which subjects received 5, 15, 50, or 150 mg of subcutaneous ixekizumab or placebo at weeks 0, 2, and 4. Results: There were significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells, and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative RT-PCR and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-alpha was of higher magnitude at 2 weeks than in prior studies with TNF-alpha antagonism. Conclusion: Our data suggest that IL-17 is a key driver'' cytokine that activates pathogenic inflammation in subjects with psoriasis. Neutralizing IL-17 with ixekizumab might be a successful therapeutic strategy in psoriasis. (J Allergy Clin Immunol 2012;130:145-54.)

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