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- Title
Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis.
- Authors
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.; Blödorn‐Schlicht, Norbert A.; Hueber, Wolfgang; Sommer, Ulrike; Schumacher, Martin M.; Peters, Thomas; Kriehuber, Ernst
- 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.
- Subjects
PSORIASIS treatment; KERATINOCYTES; MESSENGER RNA; DENDRITIC cells; NEUTROPHILS
- Publication
Experimental Dermatology, 2015, Vol 24, Issue 7, p529
- ISSN
0906-6705
- Publication type
Article
- DOI
10.1111/exd.12710