Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

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 MTH1low 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 MTH1high and MTH1low 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.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: MTH1 is up-regulated in activated human T cells, correlating with an increase in oxidative stress, but the MTH1 increase occurs before the altered redox status is fully detected.
Fig. 2: MTH1 inhibition is cytotoxic to activated T cells, whereas resting cells are unaffected.
Fig. 3: TH1579 kills T cells by inducing DNA damage in proliferating cells and pushing them towards G2/M arrest.
Fig. 4: MTH1 inhibition with TH1579 induces cytotoxicity by mitotic spindle disruption and causes 8-oxoG incorporation.
Fig. 5: MTH1 inhibition of activated T cells with TH1579 selectively kills MTH1high T cells and increases the ratio of proliferating MTH1low T cells.
Fig. 6: MTH1 inhibition with TH1579 drives the remaining surviving cells towards an MTH1low phenotype with decreased ROS levels.
Fig. 7: Non-toxicity in other immune cells.
Fig. 8: Animal studies suggest a therapeutic role of TH1579 in the T cells driven disease model of multiple sclerosis, Experimental autoimmune encephalomyelitis (EAE).

References

  1. 1.

    Hayter SM, Cook MC. Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmun Rev. 2012;11:754–65.

    PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Rosenblum MD, Gratz IK, Paw JS, Abbas AK. Treating human autoimmunity: current practice and future prospects. Sci Transl Med. 2012;4:125sr1.

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278:369–95.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Bluestone JA, Bour-Jordan H, Cheng M, Anderson M. T cells in the control of organ-specific autoimmunity. J Clin Investig. 2015;125:2250–60.

    PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74:5–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Goodnow CC, Sprent J, Fazekas de St Groth B, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005;435:590–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Li P, Zheng Y, Chen X. Drugs for autoimmune inflammatory diseases: from small molecule compounds to anti-TNF biologics. Front Pharm. 2017;8:460.

    CAS  Article  Google Scholar 

  8. 8.

    Sarzi-Puttini P, Ceribelli A, Marotto D, Batticciotto A, Atzeni F. Systemic rheumatic diseases: from biological agents to small molecules. Autoimmun Rev. 2019;18:583–92.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol. 2014;27:55–62.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Wang W, Zhou H, Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur J Med Chem. 2018;158:502–16.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Mazaud C, Fardet L. Relative risk of and determinants for adverse events of methotrexate prescribed at a low dose: a systematic review and meta‐analysis of randomized placebo‐controlled trials. Br J Dermatol (1951). 2017;177:978–86.

    CAS  Article  Google Scholar 

  12. 12.

    Quezada SM, McLean LP, Cross RK. Adverse events in IBD therapy: the 2018 update. Expert Rev Gastroenterol Hepatol. 2018;12:1183–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370:59–67.

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Nathan C, Cunningham-Bussel A. Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol. 2013;13:349–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Franchina DG, Dostert C, Brenner D. Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol. 2018;39:489–502.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Belikov AV, Schraven B, Simeoni L. T cells and reactive oxygen species. J Biomed Sci. 2015;22:85.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Simeoni L, Bogeski I. Redox regulation of T-cell receptor signaling. Biological Chem. 2015;396:555–69.

  18. 18.

    Previte DM, O’Connor EC, Novak EA, Martins CP, Mollen KP, Piganelli JD. Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4(+) T cell activation. Plos One. 2017;12:e0175549.

  19. 19.

    Buck MD, O’Sullivan D, Geltink RIK, Curtis JD, Chang CH, Sanin DE, et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 2016;166:63–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342:1242454.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013;31:259–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Developmental Biol. 2018;80:50–64.

    CAS  Article  Google Scholar 

  23. 23.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Cassim S, Vucetic M, Zdralevic M, Pouyssegur J. Warburg and beyond: the power of mitochondrial metabolism to collaborate or replace fermentative glycolysis in cancer. Cancers. 2020;12:1119.

  25. 25.

    Luo M, He H, Kelley MR, Georgiadis MM. Redox regulation of DNA repair: implications for human health and cancer therapeutic development. Antioxid Redox Signal. 2010;12:1247–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Sakumi K, Furuichi M, Tsuzuki T, Kakuma T, Kawabata S, Maki H, et al. Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis. J Biol Chem. 1993;268:23524.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Oka S, Ohno M, Tsuchimoto D, Sakumi K, Furuichi M, Nakabeppu Y. Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs.EMBO J. 2008;27:421–32.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Ichikawa J, Tsuchimoto D, Oka S, Ohno M, Furuichi M, Sakumi K, et al. Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death. DNA Repair. 2008;7:418–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Carter M, Jemth A-S, Hagenkort A, Page BDG, Gustafsson R, Griese JJ, et al. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nat Commun. 2015;6:7871.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Teruhisa T, Akinori E, Hisato I, Tomoo I, Yoko N, Yohei T, et al. Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-Oxo-dGTPase. Proc Natl Acad Sci. 2001;98:11456–61.

    Article  Google Scholar 

  31. 31.

    Oda H, Nakabeppu Y, Furuichi M, Sekiguchi M. Regulation of expression of the human MTH1 gene encoding 8-oxo-dGTPase. Alternative splicing of transcription products. J Biol Chem. 1997;272:17843–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Strom CE, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. Nature. 2014;508:215–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Warpman Berglund U, Sanjiv K, Gad H, Kalderen C, Koolmeister T, Pham T, et al. Validation and development of MTH1 inhibitors for treatment of cancer. Ann Oncol. 2016;27:2275–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Hua XW, Sanjiv K, Gad H, Pham T, Gokturk C, Rasti A, et al. Karonudib is a promising anticancer therapy in hepatocellular carcinoma. Ther Adv Med Oncol. 2019;11:1–13.

  35. 35.

    Magkouta SF, Pappas AG, Vaitsi PC, Agioutantis PC, Pateras IS, Moschos CA, et al. MTH1 favors mesothelioma progression and mediates paracrine rescue of bystander endothelium from oxidative damage. JCI Insight. 2020;5:1–16.

  36. 36.

    Brautigam L, Pudelko L, Jemth AS, Gad H, Narwal M, Gustafsson R, et al. Hypoxic signaling and the cellular redox tumor environment determine sensitivity to MTH1 Inhibition. Cancer Res. 2016;76:2366–75.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Hirahara K, Nakayama T. CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm. Int Immunol. 2016;28:163–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Zhu J. T helper cell differentiation, heterogeneity, and plasticity. Cold Spring Harb Perspect Biol. 2018;10:a030338.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Gad H, Mortusewicz O, Rudd SG, Stolz A, Amaral N, Brautigham L, et al. MTH1 promotes mitotic progression to avoid oxidative DNA damage in cancer cells. bioRxiv. 2019:10:https://doi.org/10.1101/575290.

  40. 40.

    Rudd SG, Gad H, Sanjiv K, Amaral N, Hagenkort A, Groth P, et al. MTH1 inhibitor TH588 disturbs mitotic progression and induces mitosis-dependent accumulation of genomic 8-oxodG. Cancer Res. 2020;80:3530–41.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Bivik Eding C, Köhler I, Verma D, Sjögren F, Bamberg C, Karsten S, et al. MTH1 inhibitors for the treatment of psoriasis. J Investig Dermatol. 2021;141:2037–2048.e4.

  42. 42.

    Samaranayake GJ, Troccoli CI, Zhang L, Mai H, Jayaraj CJ, Ji D, et al. The existence of MTH1-independent 8-oxodGTPase activity in cancer cells as a compensatory mechanism against on-target effects of MTH1 inhibitors. Mol Cancer Ther. 2020;19:432–46.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol.2010;28:445–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Loo TT, Gao Y, Lazarevic V. Transcriptional regulation of CD4(+) TH cells that mediate tissue inflammation. J Leukoc Biol. 2018;104:1069–85.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    O’Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998;8:275–83.

    PubMed  Article  Google Scholar 

  46. 46.

    Abimannan T, Peroumal D, Parida JR, Barik PK, Padhan P, Devadas S. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells. Free Radic Biol Med. 2016;99:352–63.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. 2019;20:55–70.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Leone RD, Powell JD. Metabolism of immune cells in cancer. Nat Rev Cancer. 2020;20:516–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Tse HM, Thayer TC, Steele C, Cuda CM, Morel L, Piganelli JD, et al. NADPH oxidase deficiency regulates Th lineage commitment and modulates autoimmunity. J Immunol. 2010;185:5247–58.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Previte DM, Piganelli JD. Reactive oxygen species and their implications on CD4(+) T cells in type 1 diabetes. Antioxid Redox Signal. 2018;29:1399–414.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Kimura K. Regulatory T cells in multiple sclerosis. Clin Exp Neuroimmunol. 2020;11:148–55.

    Article  Google Scholar 

  52. 52.

    Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, et al. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice.Am J Pathol. 2003;162:691–702.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. Faseb J. 2003;17:1195–214.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Lu R, Nash HM, Verdine GL. A mammalian DNA repair enzyme that excises oxidatively damaged guanines maps to a locus frequently lost in lung cancer. Curr Biol. 1997;7:397–407.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Hazra TK, Hill JW, Izumi T, Mitra S. Multiple DNA glycosylases for repair of 8-oxoguanine and their potential in Vivo functions. Prog Nucleic Acid Res Mol Biol. 2001;68:193–205.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    German P, Szaniszlo P, Hajas G, Radak Z, Bacsi A, Hazra TK, et al. Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair. DNA Repair. 2013;12:856–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Mabley JG, Pacher P, Deb A, Wallace R, Elder RH, Szabo C. Potential role for 8-oxoguanine DNA glycosylase in regulating inflammation. FASEB J. 2005;19:290–2.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Touati E, Michel V, Thiberge J-M, Ave P, Huerre M, Bourgade F, et al. Deficiency in OGG1 protects against inflammation and mutagenic effects associated with h. pylori infection in mouse. Helicobacter. 2006;11:494–505.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Li GP, Yuan KF, Yan CG, Fox J, Gaid M, Breitwieser W, et al. 8-Oxoguanine-DNA glycosylase 1 deficiency modifies allergic airway inflammation by regulating STAT6 and IL-4 in cells and in mice. Free Radic Biol Med. 2012;52:392–401.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Bacsi A, Aguilera-Aguirre L, Szczesny B, Radak Z, Hazra TK, Sur S, et al. Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation. DNA Repair. 2013;12:18–26.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Ba X, Aguilera-Aguirre L, Rashid QTAN, Bacsi A, Radak Z, Sur S, et al. The role of 8-oxoguanine DNA glycosylase-1 in inflammation. Int J Mol Sci. 2014;15:16975–97.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Visnes T, Cazares-Korner A, Hao WJ, Wallner O, Masuyer G, Loseva O, et al. Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science 2018;362:834. +

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Qin S, Lin P, Wu Q, Pu Q, Zhou C, Wang B, et al. Small-molecule inhibitor of 8-oxoguanine DNA glycosylase 1 regulates inflammatory responses during pseudomonas aeruginosa infection. J Immunol (1950). 2020;205:ji1901533–2242.

    Google Scholar 

  64. 64.

    Stratigopoulou M, van Dam TP, Guikema JEJ. Base excision repair in the immune system: small DNA lesions with big consequences. Front Immunol. 2020;11:1084.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Pazzaglia S, Pioli C. Multifaceted role of PARP-1 in DNA repair and inflammation: pathological and therapeutic implications in cancer and non-cancer diseases. Cells (Basel, Switz). 2019;9:41.

    Google Scholar 

  66. 66.

    Pateras IS, Havaki S, Nikitopoulou X, Vougas K, Townsend PA, Panayiotidis MI, et al. The DNA damage response and immune signaling alliance: Is it good or bad? Nature decides when and where. Pharm Ther. 2015;154:36–56.

    CAS  Article  Google Scholar 

  67. 67.

    Nakad R, Schumacher B. DNA damage response and immune defense: links and mechanisms. Front Genet. 2016;7:147.

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Kay J, Thadhani E, Samson L, Engelward B. Inflammation-induced DNA damage, mutations and cancer. DNA repair. 2019;83:102673.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Bhattacharya S, Srinivasan K, Abdisalaam S, Su F, Raj P, Dozmorov I, et al. RAD51 interconnects between DNA replication, DNA repair and immunity. Nucleic Acids Res. 2017;45:4590–605.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Sahraian MA, Soltani BM, Behmanesh M. Alteration of OGG1, MYH and MTH1 genes expression in relapsing-remitting multiple sclerosis patients. Physiol Pharmacol. 2017;21:129–36.

    Google Scholar 

  71. 71.

    Kumagae Y, Hirahashi M, Takizawa K, Yamamoto H, Gushima M, Esaki M, et al. Overexpression of MTH1 and OGG1 proteins in ulcerative colitis-associated carcinogenesis. Oncol Lett. 2018;16:1765–76.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Sakumi K, Tominaga Y, Furuichi M, Xu P, Tsuzuki T, Sekiguchi M, et al. Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption. Cancer Res. 2003;63:902–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8:24–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Sintchak MD, Fleming MA, Futer O, Raybuck SA, Chambers SP, Caron PR, et al. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell. 1996;85:921–30.

    PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Al-Badr AA, Ajarim TDS. Ganciclovir. Profiles Drug Substances Excip Relat Methodol. 2018;43:1–208.

    CAS  Article  Google Scholar 

  76. 76.

    Beck S, Zhu Z, Oliveira MF, Smith DM, Rich JN, Bernatchez JA, et al. Mechanism of action of methotrexate against Zika Virus. Viruses 2019;11:338.

    CAS  PubMed Central  Article  Google Scholar 

  77. 77.

    Einarsdottir BO, Karlsson J, Soderberg EMV, Lindberg MF, Funck-Brentano E, Jespersen H, et al. A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma. Cell Death Dis. 2018;9:810.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, et al. Multiple sclerosis. Nat Rev Dis Prim. 2018;4:43.

    PubMed  Article  Google Scholar 

  79. 79.

    Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15:545–58.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank our chemists Martin Scobie, Tobias Koolmeister, Olov Wallner and Martin Henriksson for all the work on the chemistry side, not the least synthesizing the MTH1 inhibitors. We thank Nadilly Bonagas and Aleksandra Pettke for valuable methodological input and all the members of the Helleday laboratory for discussion and support. We thank Weng-Onn Lui at the flow cytometry lab of the Department of Oncology-Pathology for technical assistance and support.

Funding

This work was funded by Karolinska Institute via its CSTP program and research internship program (forskar-AT), The European Research Council (TAROX Programme, ERC-695376, TH), The Swedish Research Council (2015-00162, 2017-06095), and the Torsten and Ragnar Söderberg Foundation (TH).

Author information

Affiliations

Authors

Contributions

RF, SK, TH, and UWB devised the concept of the study; UWB, RF, KC, CK, and LB supervised the project. SK, RF, PM, MMS, CS, KS, KC, IA, and CK designed, performed and/or analyzed cell biological experiments. XZ, RH, SK, AR, TP, KC, CS, BP, UWB designed, performed and/or analyzed in vivo experiments. SK compiled data and prepared the figures; SK drafted the manuscript supervised by UWB, CK, and TH; all authors reviewed the final manuscript.

Corresponding authors

Correspondence to Stella Karsten or Ulrika Warpman Berglund.

Ethics declarations

Competing interests

A patent has been filed with data generated in this manuscript, where TH is listed as one of the inventors. The patent is fully owned by a non-profit public foundation, the Helleday Foundation for medical research (THF), and TH and UWB are members of THF board. Oxcia AB has license to the patent and perform clinical development of TH1579. UWB is CEO of Oxcia AB, TH is board member of Oxcia AB. The other authors declare no conflict of interest.

Ethics approval

This study was performed in accordance with the Declaration of Helsinki. The in vitro experiments on human T cells were performed on products from buffy coats extracted from blood products donated by healthy donors for the blood banks of the Karolinska University Hospital (Stockholm, Sweden), where no additional intervention was performed on the donors specifically for this research. There was no possibility to trace back the samples to the donors. The in vivo studies were approved by the local ethical committees (Stockholm North, number N138/14 for the EAE study; Stockholm South, number S7-15 for the TDAR study).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Edited by G. Melino

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Karsten, S., Fiskesund, R., Zhang, XM. et al. MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells. Cell Death Differ (2021). https://doi.org/10.1038/s41418-021-00854-4

Download citation

Search

Quick links