Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis.

Abstract

The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil-keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL-17A-directed therapies such as secukinumab.

• Authors: Kristian Reich, Kim A Papp, Robert T Matheson, John H Tu, Robert Bissonnette, Marc Bourcier, David Gratton, Rodion A Kunynetz, Yves Poulin, Les A Rosoph, Georg Stingl, Wolfgang M Bauer, Janeen M Salter, Thomas M Falk, Norbert A Blödorn-Schlicht, Wolfgang Hueber, Ulrike Sommer, Martin M Schumacher, Thomas Peters, Ernst Kriehuber, David M Lee, Grazyna A Wieczorek, Frank Kolbinger, Conrad C Bleul
• Journal: Experimental dermatology (Exp Dermatol) Vol. 24 Issue 7 Pg. 529-35 (Jul 2015) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 25828362 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Experimental Dermatology Published by John Wiley & Sons Ltd.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• IL17A protein, human
• Interleukin-17
• secukinumab

Topics

• Adolescent
• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Humanized
• Cell Communication (immunology)
• Dose-Response Relationship, Immunologic
• Humans
• Interleukin-17 (antagonists & inhibitors)
• Keratinocytes (immunology, pathology)
• Middle Aged
• Neutrophils (immunology, pathology)
• Psoriasis (immunology, pathology, therapy)
• Time Factors
• Young Adult