Exp Dermatol. 2015 Jul;24(7):529-35. doi: 10.1111/exd.12710.

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

 

Reich K1, Papp KA2, Matheson RT3, Tu JH4, Bissonnette R5, Bourcier M6, Gratton D7, Kunynetz RA8, Poulin Y9, Rosoph LA10, Stingl G11, Bauer WM11, Salter JM12, Falk TM1, Blödorn-Schlicht NA1, Hueber W12, Sommer U12, Schumacher MM12, Peters T12, Kriehuber E12, Lee DM12, Wieczorek GA12, Kolbinger F12, Bleul CC12.
  • 1Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany.
  • 2Probity Medical Research Inc, Waterloo, ON, Canada.
  • 3Oregon Medical Research Center PC, Portland, OR, USA.
  • 4Skin Search of Rochester, Rochester, NY, USA.
  • 5Innovaderm Research Inc, Montreal, QC, Canada.
  • 6Dermatology Clinic, Moncton, NB, Canada.
  • 7International Dermatology Research, Montreal, QC, Canada.
  • 8Ultranova Skincare, Barrie, ON, Canada.
  • 9Centre de Recherche Dermatologique du Québec Métropolitain, Quebec City, QC, Canada.
  • 10North Bay Dermatology Centre, North Bay, ON, Canada.
  • 11Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
  • 12Novartis Institutes for BioMedical Research, Basel, Switzerland.

 

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.

KEYWORDS: IL-17A; neutrophils; psoriasis; secukinumab

PMID: 25828362

 

 

 

 

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