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Targeting Costimulatory Pathways in Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype condition for studying the links between autoimmunity and fibrosis. Costimulatory pathways such as CD28/CTLA-4, ICOS-B7RP1, CD70-CD27...

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Autores principales: Boleto, Gonçalo, Allanore, Yannick, Avouac, Jérôme
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305435/
https://www.ncbi.nlm.nih.gov/pubmed/30619351
http://dx.doi.org/10.3389/fimmu.2018.02998
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author Boleto, Gonçalo
Allanore, Yannick
Avouac, Jérôme
author_facet Boleto, Gonçalo
Allanore, Yannick
Avouac, Jérôme
author_sort Boleto, Gonçalo
collection PubMed
description Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype condition for studying the links between autoimmunity and fibrosis. Costimulatory pathways such as CD28/CTLA-4, ICOS-B7RP1, CD70-CD27, CD40-CD154, or OX40-OX40L play an essential role in the modulation of T-cell and inflammatory immune responses. A growing body of evidence suggests that T-cell costimulation signals might be implicated in the pathogenesis of SSc. CD28, CTLA-4, ICOS, and OX40L are overexpressed in patients with SSc, particularly in patients with cutaneous diffuse forms. In pre-clinical models of SSc, T-cell costimulation blockade with abatacept (CTLA-4-Ig) prevented and induced the regression of inflammation-driven dermal fibrosis, improved digestive involvement, prevented lung fibrosis, and attenuated pulmonary hypertension in complementary models of SSc. Likewise, potent anti-fibrotic effects were seen with the blockade of OX40L by reducing the infiltration of inflammatory cells into lesional tissues leading to decreased fibroblast activation. Concerning clinical effects, a preliminary observational study suggested some effectiveness of abatacept on inflammatory joint involvement, whereas clinical improvement of skin fibrosis was observed in a small placebo-controlled randomized trial. Currently there is one ongoing phase II clinical trial assessing the efficacy of abatacept in SSc (ASSET trial, NCT02161406). Overall, given the lack of available effective agents and the known toxic effects of immunosuppressive agents approved for use in SSc, costimulatory pathways offer the advantage of a targeted approach to costimulatory signals and potentially a better safety profile.
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spelling pubmed-63054352019-01-07 Targeting Costimulatory Pathways in Systemic Sclerosis Boleto, Gonçalo Allanore, Yannick Avouac, Jérôme Front Immunol Immunology Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype condition for studying the links between autoimmunity and fibrosis. Costimulatory pathways such as CD28/CTLA-4, ICOS-B7RP1, CD70-CD27, CD40-CD154, or OX40-OX40L play an essential role in the modulation of T-cell and inflammatory immune responses. A growing body of evidence suggests that T-cell costimulation signals might be implicated in the pathogenesis of SSc. CD28, CTLA-4, ICOS, and OX40L are overexpressed in patients with SSc, particularly in patients with cutaneous diffuse forms. In pre-clinical models of SSc, T-cell costimulation blockade with abatacept (CTLA-4-Ig) prevented and induced the regression of inflammation-driven dermal fibrosis, improved digestive involvement, prevented lung fibrosis, and attenuated pulmonary hypertension in complementary models of SSc. Likewise, potent anti-fibrotic effects were seen with the blockade of OX40L by reducing the infiltration of inflammatory cells into lesional tissues leading to decreased fibroblast activation. Concerning clinical effects, a preliminary observational study suggested some effectiveness of abatacept on inflammatory joint involvement, whereas clinical improvement of skin fibrosis was observed in a small placebo-controlled randomized trial. Currently there is one ongoing phase II clinical trial assessing the efficacy of abatacept in SSc (ASSET trial, NCT02161406). Overall, given the lack of available effective agents and the known toxic effects of immunosuppressive agents approved for use in SSc, costimulatory pathways offer the advantage of a targeted approach to costimulatory signals and potentially a better safety profile. Frontiers Media S.A. 2018-12-18 /pmc/articles/PMC6305435/ /pubmed/30619351 http://dx.doi.org/10.3389/fimmu.2018.02998 Text en Copyright © 2018 Boleto, Allanore and Avouac. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Boleto, Gonçalo
Allanore, Yannick
Avouac, Jérôme
Targeting Costimulatory Pathways in Systemic Sclerosis
title Targeting Costimulatory Pathways in Systemic Sclerosis
title_full Targeting Costimulatory Pathways in Systemic Sclerosis
title_fullStr Targeting Costimulatory Pathways in Systemic Sclerosis
title_full_unstemmed Targeting Costimulatory Pathways in Systemic Sclerosis
title_short Targeting Costimulatory Pathways in Systemic Sclerosis
title_sort targeting costimulatory pathways in systemic sclerosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305435/
https://www.ncbi.nlm.nih.gov/pubmed/30619351
http://dx.doi.org/10.3389/fimmu.2018.02998
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