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Hipp, H. ; Tondello, C. ; Gmehling, H. ; Scholz, L.K.* ; Stavridou, A.* ; Becker, M. ; Bührer, A.-M. ; Hintermann, E.* ; Dirschl, S.M. ; Johannsmann, T.M. ; Scherm, M.G. ; Kohlhof, H.* ; Serr, I. ; Christen, U.* ; Daniel, C.

Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes.

Mol. Metab. 100:102218 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: In autoimmune Type 1 Diabetes (T1D), aberrant immune activation promotes regulatory T cell (Treg) impairments thereby boosting progression of islet autoimmunity. Consequently, there is a progressive destruction of the insulin-producing beta cells in the pancreas. Controlling overshooting immune activation represents a relevant approach to allow for efficient Treg-targeting by broadening the window of opportunity to induce Tregs. METHODS: We investigated the effect of restricting pyrimidine de novo synthesis during islet autoimmunity and T1D by Dihydroorotate dehydrogenase (DHODH) inhibition using the next-generation DHODH inhibitor Vidofludimus calcium. We assessed Treg-inducing features of DHODH inhibition in T cells from ongoing murine islet autoimmunity and human T1D in vitro. To dissect the functional relevance of these observations, we tested the impact of DHODH inhibition on interfering with autoimmune activation and disease progression in pre-clinical models of T1D in vivo. MAIN FINDINGS: We show that DHODH inhibition results in enhanced Treg induction in vitro especially during increased immune activation and reduced T cell proliferation. In addition, Vidofludimus calcium reduced T1D incidence in two mouse models. On the cellular level, treated mice showed reduced T cell activation accompanied by increased Treg frequencies. CONCLUSIONS: We demonstrate that restricting pyrimidine de novo synthesis by next-generation DHODH inhibition is a strategy to interfere with autoimmune activation while fostering Tregs.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autoimmunity ; Dhodh Inhibition ; Immunomodulation ; Mouse Model ; Regulatory T Cells ; Type 1 Diabetes ; Vidofludimus Calcium; Regulatory T-cells; Proinflammatory Il-17(+); Foxp3; Differentiation; Expression; Effector; Mellitus; Onset; Mice
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Journal Molecular Metabolism
Quellenangaben Volume: 100, Issue: , Pages: , Article Number: 102218 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Reviewing status Peer reviewed
Institute(s) Research Unit Type 1 Diabetes Immunology (TDI)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502191-001
Grants Projekt DEAL
Research Group at Helmholtz Zentrum Muenchen
CRC1054 of the Deutsche Forschungsgemeinschaft
Deutsche Forschungsgemeinschaft - Helmholtz Munich Innovation and Translation Fund
Helmholtz Association-Initiative and Networking Fund (IVF)
International Helmholtz Research School for Diabetes
Ludwig-Maximilians-Universitaet Muenchen
Transcampus IRTG 2251: "Immunological and Cellular Strategies in Metabolic Disease" (ICSMD) (Deutsche Forschungsgemeinschaft
German Center for Diabetes Research (DZD)
Fritz Bender Stiftung granted
Excellence Program for Outstanding Female Scientists from the Helmholtz Association
DOI 10.1016/j.molmet.2025.102218
WOS ID 001550219800001
Scopus ID 105012375637
PubMed ID 40706797
Erfassungsdatum 2025-07-28
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