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

J Allergy Clin Immunol, 2012/7;130(1):145-54.e9.

Krueger JG[1], Fretzin S, Suárez-Fariñas M, Haslett PA, Phipps KM, Cameron GS, McColm J, Katcherian A, Cueto I, White T, Banerjee S, Hoffman RW

Affiliations

PMID: 22677045DOI: 10.1016/j.jaci.2012.04.024

Impact factor: 14.29

Abstract
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 (previously LY2439821) 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-α was of higher magnitude at 2 weeks than in prior studies with TNF-α 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.
MeSH terms
Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dose-Response Relationship, Drug; Humans; Inflammation; Interleukin-17; Lymphocyte Activation; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Psoriasis; Reverse Transcriptase Polymerase Chain Reaction; Skin; Th17 Cells; Treatment Outcome; Tumor Necrosis Factor-alpha
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