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Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways

Immune responses against gene therapy products limit its therapeutic efficacy and present a safety risk. Identification of agents that blunt immune reactions may aid in developing novel immunomodulatory therapies. Fingolimod (FTY720) is an FDA approved immunomodulatory drug for treating multiple scl...

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Autores principales: Baer, Alan, Colon-Moran, Winston, Bhattarai, Nirjal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053412/
https://www.ncbi.nlm.nih.gov/pubmed/30026610
http://dx.doi.org/10.1038/s41598-018-29355-0
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author Baer, Alan
Colon-Moran, Winston
Bhattarai, Nirjal
author_facet Baer, Alan
Colon-Moran, Winston
Bhattarai, Nirjal
author_sort Baer, Alan
collection PubMed
description Immune responses against gene therapy products limit its therapeutic efficacy and present a safety risk. Identification of agents that blunt immune reactions may aid in developing novel immunomodulatory therapies. Fingolimod (FTY720) is an FDA approved immunomodulatory drug for treating multiple sclerosis that inhibits lymphocyte egress from lymphoid tissues by down regulating sphingosine-1 phosphate receptor (S1PR). Recent studies found that FTY720 inhibits T cell activation (TCA) in a S1PR-independent manner; however, the mechanism is incompletely understood. Here we characterized the effects of FTY720 on human T cell receptor (TCR) signaling pathways. FTY720 inhibited both the TCR-dependent and independent activation of primary human T cells. FTY720 did not affect proximal TCR signaling events as measured by phosphorylation of Lck, ZAP-70 and LAT; however, inhibited PMA/Ionomycin induced distal TCR signaling as measured by IL-2, IFN-γ release and CD25 expression. FTY720 induced aberrant NFAT1, AP1 and NFκB activation which were associated with increased acetylation of histone (H3K9). Phosphorylated FTY720 did not inhibit TCA, and arachidonic acid did not rescue FTY720 mediated inhibition of TCA. These data suggest that FTY720 mediated inhibition of TCA is due to inhibition of distal TCR signaling. Understanding FTY720-mediated inhibition of TCA may aid in developing novel FTY720-based immunomodulatory agents.
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spelling pubmed-60534122018-07-23 Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways Baer, Alan Colon-Moran, Winston Bhattarai, Nirjal Sci Rep Article Immune responses against gene therapy products limit its therapeutic efficacy and present a safety risk. Identification of agents that blunt immune reactions may aid in developing novel immunomodulatory therapies. Fingolimod (FTY720) is an FDA approved immunomodulatory drug for treating multiple sclerosis that inhibits lymphocyte egress from lymphoid tissues by down regulating sphingosine-1 phosphate receptor (S1PR). Recent studies found that FTY720 inhibits T cell activation (TCA) in a S1PR-independent manner; however, the mechanism is incompletely understood. Here we characterized the effects of FTY720 on human T cell receptor (TCR) signaling pathways. FTY720 inhibited both the TCR-dependent and independent activation of primary human T cells. FTY720 did not affect proximal TCR signaling events as measured by phosphorylation of Lck, ZAP-70 and LAT; however, inhibited PMA/Ionomycin induced distal TCR signaling as measured by IL-2, IFN-γ release and CD25 expression. FTY720 induced aberrant NFAT1, AP1 and NFκB activation which were associated with increased acetylation of histone (H3K9). Phosphorylated FTY720 did not inhibit TCA, and arachidonic acid did not rescue FTY720 mediated inhibition of TCA. These data suggest that FTY720 mediated inhibition of TCA is due to inhibition of distal TCR signaling. Understanding FTY720-mediated inhibition of TCA may aid in developing novel FTY720-based immunomodulatory agents. Nature Publishing Group UK 2018-07-19 /pmc/articles/PMC6053412/ /pubmed/30026610 http://dx.doi.org/10.1038/s41598-018-29355-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Baer, Alan
Colon-Moran, Winston
Bhattarai, Nirjal
Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways
title Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways
title_full Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways
title_fullStr Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways
title_full_unstemmed Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways
title_short Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways
title_sort characterization of the effects of immunomodulatory drug fingolimod (fty720) on human t cell receptor signaling pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053412/
https://www.ncbi.nlm.nih.gov/pubmed/30026610
http://dx.doi.org/10.1038/s41598-018-29355-0
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