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

Autor: Karsten S; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. stella.karsten@scilifelab.se., Fiskesund R; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Department of Medicine, Karolinska Institutet, Huddinge, Sweden., Zhang XM; Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden., Marttila P; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Sanjiv K; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Pham T; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Rasti A; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Bräutigam L; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Comparative Medicine, Karolinska Institutet, Stockholm, Sweden., Almlöf I; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Marcusson-Ståhl M; RISE Research Institutes of Sweden, Unit for Chemical and Pharmaceutical safety, Södertälje, Sweden., Sandman C; RISE Research Institutes of Sweden, Unit for Chemical and Pharmaceutical safety, Södertälje, Sweden., Platzack B; RISE Research Institutes of Sweden, Unit for Chemical and Pharmaceutical safety, Södertälje, Sweden., Harris RA; Applied Immunology and Immunotherapy, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden., Kalderén C; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Cederbrant K; RISE Research Institutes of Sweden, Unit for Chemical and Pharmaceutical safety, Södertälje, Sweden., Helleday T; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Weston Park Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK., Warpman Berglund U; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. ulrika.warpmanberglund@scilifelab.se.; Oxcia AB, Stockholm, Sweden. ulrika.warpmanberglund@scilifelab.se.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2022 Jan; Vol. 29 (1), pp. 246-261.
DOI: 10.1038/s41418-021-00854-4
Abstrakt: 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 up-regulate 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 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 high and MTH1 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.
(© 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
Databáze: MEDLINE
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