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  • 1.
    Karsten, Stella
    et al.
    Karolinska Institute, Sweden.
    Fiskesund, Roland
    Karolinska Institute, Sweden.
    Zhang, Xing-Mei
    Karolinska Institute, Sweden.
    Marttila, Petra
    Karolinska Institute, Sweden.
    Sanjiv, Kumar
    Karolinska Institute, Sweden.
    Pham, Therese
    Karolinska Institute, Sweden.
    Rasti, Azita
    Karolinska Institute, Sweden.
    Bräutigam, Lars
    Karolinska Institute, Sweden.
    Almlöf, Ingrid
    Karolinska Institute, Sweden.
    Marcusson-Ståhl, Maritha
    Sandman, Carolina
    Platzack, Björn
    RISE Research Institutes of Sweden, Bioekonomi och hälsa, Kemiska processer och läkemedel.
    Harris, Robert A.
    Karolinska Institute, Sweden.
    Kalderén, Christina
    Karolinska Institute, Sweden.
    Cederbrant, Karin
    Helleday, Thomas
    Karolinska Institute, Sweden; University of Sheffield, United Kingdom.
    Warpman Berglund, Ulrika
    Karolinska Institute, Sweden; Oxcia AB, Sweden.
    MTH1 as a target to alleviate T cell driven diseases by selective suppression of activated T cells2022Ingår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 29, nr 1, s. 246-261Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 2.
    Turley, Joanna
    et al.
    Trinity College Dublin, Ireland.
    Moran, Hanna
    Trinity College Dublin, Ireland.
    McEntee, Craig
    Trinity College Dublin, Ireland.
    O'Grady, Katie
    Trinity College Dublin, Ireland.
    Muñoz-Wolf, Natalia
    Trinity College Dublin, Ireland.
    Jin, Lei
    University of Florida, USA.
    Follmann, Frank
    Statens Serum Institute, Denmark.
    Andersen, Peter
    Statens Serum Institute, Denmark.
    Andersson, Mats
    RISE Research Institutes of Sweden.
    Lavelle, Ed
    Trinity College Dublin, Ireland.
    Chitin-derived polymer deacetylation regulates mitochondrial reactive oxygen species dependent cGAS-STING and NLRP3 inflammasome activation2021Ingår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 275, artikel-id 120961Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chitosan is a cationic polysaccharide that has been evaluated as an adjuvant due to its biocompatible and biodegradable nature. The polysaccharide can enhance antibody responses and cell-mediated immunity following vaccination by injection or mucosal routes. However, the optimal polymer characteristics for activation of dendritic cells (DCs) and induction of antigen-specific cellular immune responses have not been resolved. Here, we demonstrate that only chitin-derived polymers with a high degree of deacetylation (DDA) enhance generation of mitochondrial reactive oxygen species (mtROS), leading to cGAS-STING mediated induction of type I IFN. Additionally, the capacity of the polymers to activate the NLRP3 inflammasome was strictly dependent on the degree and pattern of deacetylation and mtROS generation. Polymers with a DDA below 80% are poor adjuvants while a fully deacetylated polyglucosamine polymer is most effective as a vaccine adjuvant. Furthermore, this polyglucosamine polymer enhanced antigen-specific Th1 responses in a NLRP3 and STING-type I IFN-dependent manner. Overall these results indicate that the degree of chitin deacetylation, the acetylation pattern and its regulation of mitochondrial ROS are the key determinants of its immune enhancing effects. © 2021 The Author(s)

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