Show simple item record

dc.contributor.authorHammitzsch, Ariane
dc.contributor.authorChen, Liye
dc.contributor.authorde Wit, Jelle
dc.contributor.authorAl-Mossawi, M Hussein
dc.contributor.authorRidley, Anna
dc.contributor.authorSekine, Takuya
dc.contributor.authorSimone, Davide
dc.contributor.authorDoig, Karen
dc.contributor.authorSkapenko, Alla
dc.contributor.authorBowness, Paul
dc.date.accessioned2018-11-20T12:08:17Z
dc.date.available2018-11-20T12:08:17Z
dc.date.issued2018-10-23
dc.identifier.citationInhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases. 2018, 8 (1):15645 Sci Repen
dc.identifier.issn2045-2322
dc.identifier.pmid30353145
dc.identifier.doi10.1038/s41598-018-34026-1
dc.identifier.urihttp://hdl.handle.net/10029/622305
dc.description.abstractTreatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFNγ were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS.
dc.language.isoenen
dc.rightsArchived with thanks to Scientific reportsen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleInhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases.en
dc.identifier.journalSci Rep 2018; 8(1):15645en
refterms.dateFOA2018-12-18T14:36:47Z
html.description.abstractTreatment options for Ankylosing Spondylitis (AS) are still limited. The T helper cell 17 (Th17) pathway has emerged as a major driver of disease pathogenesis and a good treatment target. Janus kinases (JAK) are key transducers of cytokine signals in Th17 cells and therefore promising targets for the treatment of AS. Here we investigate the therapeutic potential of four different JAK inhibitors on cells derived from AS patients and healthy controls, cultured in-vitro under Th17-promoting conditions. Levels of IL-17A, IL-17F, IL-22, GM-CSF and IFNγ were assessed by ELISA and inhibitory effects were investigated with Phosphoflow. JAK1/2/3 and TYK2 were silenced in CD4+ T cells with siRNA and effects analyzed by ELISA (IL-17A, IL-17F and IL-22), Western Blot, qPCR and Phosphoflow. In-vitro inhibition of CD4+ T lymphocyte production of multiple Th17 cytokines (IL-17A, IL-17F and IL-22) was achieved with JAK inhibitors of differing specificity, as well as by silencing of JAK1-3 and Tyk2, without impacting on cell viability or proliferation. Our preclinical data suggest JAK inhibitors as promising candidates for therapeutic trials in AS, since they can inhibit multiple Th17 cytokines simultaneously. Improved targeting of TYK2 or other JAK isoforms may confer tailored effects on Th17 responses in AS.


Files in this item

Thumbnail
Name:
s41598-018-34026-1.pdf
Size:
2.336Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Archived with thanks to Scientific reports
Except where otherwise noted, this item's license is described as Archived with thanks to Scientific reports