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Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL ‐17A inhibition in psoriasis
Author(s) -
Reich Kristian,
Papp Kim A.,
Matheson Robert T.,
Tu John H.,
Bissonnette Robert,
Bourcier Marc,
Gratton David,
Kunynetz Rodion A.,
Poulin Yves,
Rosoph Les A.,
Stingl Georg,
Bauer Wolfgang M.,
Salter Janeen M.,
Falk Thomas M.,
BlödornSchlicht Norbert A.,
Hueber Wolfgang,
Sommer Ulrike,
Schumacher Martin M.,
Peters Thomas,
Kriehuber Ernst,
Lee David M.,
Wieczorek Grazyna A.,
Kolbinger Frank,
Bleul Conrad C.
Publication year - 2015
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12710
Subject(s) - psoriasis , secukinumab , cxcl1 , interleukin 17 , immunology , medicine , cytokine , keratinocyte , chemokine , interleukin 8 , chemotaxis , cd11c , inflammation , biology , receptor , in vitro , psoriatic arthritis , biochemistry , gene , phenotype
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. CXCL 1 , CXCL 8 ); effects on numbers of T cells and CD 11c‐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.