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  • Karsten, StellaKarolinska Institutet,Karolinska Institute, Sweden (author)

MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • 2021-08-27
  • Stockholm :Karolinska Institutet, Dept of Oncology-Pathology,2021
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:openarchive.ki.se:10616/47733
  • ISSN:1350-9047
  • 10616/47733hdl
  • http://hdl.handle.net/10616/47733URI
  • https://doi.org/10.1038/s41418-021-00854-4DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:147485282URI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:ri:diva-56298URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • T cell-driven diseases account for considerable morbidity and disability globally and there is an urgent need for new targeted therapies. Both cancer cells and activated T cells have an altered redox balance, and up-regulate the DNA repair protein MTH1 that sanitizes the oxidized nucleotide pool to avoid DNA damage and cell death. Herein we suggest that the up-regulation of MTH1 in activated T cells correlates with their redox status, but occurs before the ROS levels increase, challenging the established conception of MTH1 increasing as a direct response to an increased ROS status. We also propose a heterogeneity in MTH1 levels among activated T cells, where a smaller subset of activated T cells does not upregulate MTH1 despite activation and proliferation. The study suggests that the vast majority of activated T cells have high MTH1 levels and are sensitive to the MTH1 inhibitor TH1579 (Karonudib) via induction of DNA damage and cell cycle arrest. TH1579 further drives the surviving cells to the MTH1[superscript low] phenotype with altered redox status. TH1579 does not affect resting T cells, as opposed to the established immunosuppressor Azathioprine, and no sensitivity among other major immune cell types regarding their function can be observed. Finally, we demonstrate a therapeutic effect in a murine model of experimental autoimmune encephalomyelitis. In conclusion, we show proof of concept of the existence of MTH1[superscript high] and MTH1[superscript low] activated T cells, and that MTH1 inhibition by TH1579 selectively suppresses pro-inflammatory activated T cells. Thus, MTH1 inhibition by TH1579 may serve as a novel treatment option against autoreactive T cells in autoimmune diseases, such as multiple sclerosis.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Fiskesund, RolandKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Zhang, Xing-MeiKarolinska Institute, Sweden (author)
  • Marttila, PetraKarolinska Institute, Sweden (author)
  • Sanjiv, KumarKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Pham, ThereseKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Rasti, AzitaKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Bräutigam, LarsKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Almlöf, IngridKarolinska Institutet,Karolinska Institute, Sweden (author)
  • Marcusson-Ståhl, Maritha (author)
  • Sandman, Carolina (author)
  • Platzack, BjörnRISE,Kemiska processer och läkemedel(Swepub:ri)bjorn.platzack@ri.se (author)
  • Harris, Robert AKarolinska Institute, Sweden (author)
  • Kalderén, ChristinaKarolinska Institute, Sweden (author)
  • Cederbrant, Karin (author)
  • Helleday, ThomasKarolinska Institutet,Karolinska Institute, Sweden; University of Sheffield, United Kingdom (author)
  • Warpman Berglund, UlrikaKarolinska Institutet,Karolinska Institute, Sweden; Oxcia AB, Sweden (author)
  • Karolinska InstitutetKarolinska Institute, Sweden (creator_code:org_t)
  • Karolinska Institutet
  • Karolinska Institutet

Related titles

  • In:Cell Death & DifferentiationStockholm : Karolinska Institutet, Dept of Oncology-Pathology1350-90471476-5403

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