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

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 in...

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Autores principales: 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, Lee, David M, Wieczorek, Grazyna A, Kolbinger, Frank, Bleul, Conrad C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676308/
https://www.ncbi.nlm.nih.gov/pubmed/25828362
http://dx.doi.org/10.1111/exd.12710
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author 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
Lee, David M
Wieczorek, Grazyna A
Kolbinger, Frank
Bleul, Conrad C
author_facet 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
Lee, David M
Wieczorek, Grazyna A
Kolbinger, Frank
Bleul, Conrad C
author_sort Reich, Kristian
collection PubMed
description 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.
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spelling pubmed-46763082015-12-19 Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis 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 Lee, David M Wieczorek, Grazyna A Kolbinger, Frank Bleul, Conrad C Exp Dermatol Original Articles 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. John Wiley & Sons, Ltd 2015-07 2015-05-08 /pmc/articles/PMC4676308/ /pubmed/25828362 http://dx.doi.org/10.1111/exd.12710 Text en © 2015 The Authors. Experimental Dermatology Published by John Wiley & Sons Ltd. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
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
Lee, David M
Wieczorek, Grazyna A
Kolbinger, Frank
Bleul, Conrad C
Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis
title Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis
title_full Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis
title_fullStr Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis
title_full_unstemmed Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis
title_short Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis
title_sort evidence that a neutrophil–keratinocyte crosstalk is an early target of il-17a inhibition in psoriasis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676308/
https://www.ncbi.nlm.nih.gov/pubmed/25828362
http://dx.doi.org/10.1111/exd.12710
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