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

• Published in: Journal of allergy and clinical immunology Vol. 130; no. 1; pp. 145 - 154.e9
• Main Authors: Krueger, James G., MD, Fretzin, Scott, MD, Suárez-Fariñas, Mayte, PhD, Haslett, Patrick A., MB, BS, Phipps, Krista M, Cameron, Gregory S., PhD, McColm, Juliet, MD, Katcherian, Artemis, Cueto, Inna, White, Traci, Banerjee, Subhashis, MD, Hoffman, Robert W., DO
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-07-2012; Elsevier; Elsevier Limited
• Subjects: Allergy and Immunology; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - therapeutic use; Biological and medical sciences; Chemokines; Clinical trials; Cloning; Dermatology; Dose-Response Relationship, Drug; Drug dosages; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Humans; IL-17; Immunopathology; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interleukin-17 - genetics; Interleukin-17 - immunology; Interleukin-17 - metabolism; Lymphocyte Activation; Lymphocytes; Medical sciences; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Pathogenesis; Psoriasis; Psoriasis - immunology; Psoriasis - physiopathology; Psoriasis - therapy; Psoriasis. Parapsoriasis. Lichen; Reverse Transcriptase Polymerase Chain Reaction; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin; Skin - immunology; Skin - metabolism; Skin - physiopathology; TH17 cells; Th17 Cells - immunology; TNF; Treatment Outcome; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; PASI; At least a 75% improvement in PASI score; Psoriasis; T H17 cells; Differentially expressed gene; IL-17; DEG; PASI 75; Dendritic cell-lysosomal associated membrane protein; DC-LAMP; TNF; Psoriasis Area and Severity Index; TH17 cells; Human; Immunopathology; Skin disease; Cytokine; Helper cell; Activation; Circuit; Inflammation; Interleukin 17; Immunology; Gene; T; Tumor necrosis factor; Genetics; 17 cells; Th17 lymphocyte
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.04.024

Background In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell–derived cytokines. Evidence suggests that the TH 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.