Hipp Hannah, Tondello Camilla, Gmehling Hanna, Scholz Lena K, Stavridou Antigoni, Becker Maike, Bührer Anne-Marie, Hintermann Edith, Dirschl Sandra M, Johannsmann Till M, Scherm Martin G, Kohlhof Hella, Serr Isabelle, Christen Urs, Daniel Carolin
Research Unit Type 1 Diabetes Immunology, Helmholtz Diabetes Center at Helmholtz Zentrum München, Munich, Germany; Deutsches Zentrum für Diabetesforschung (DZD), Munich, Germany.
Pharmazentrum Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany.
Mol Metab. 2025 Oct;100:102218. doi: 10.1016/j.molmet.2025.102218. Epub 2025 Jul 22.
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.
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.
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.
We demonstrate that restricting pyrimidine de novo synthesis by next-generation DHODH inhibition is a strategy to interfere with autoimmune activation while fostering Tregs.
在自身免疫性1型糖尿病（T1D）中，异常的免疫激活会促进调节性T细胞（Treg）功能受损，从而加速胰岛自身免疫的进展。因此，胰腺中产生胰岛素的β细胞会逐渐遭到破坏。控制过度的免疫激活是一种相关方法，可通过扩大诱导Treg的机会窗口来实现对Treg的有效靶向作用。
我们使用新一代二氢乳清酸脱氢酶（DHODH）抑制剂维托鲁胺钙，研究了在胰岛自身免疫和T1D过程中抑制嘧啶从头合成的效果。我们在体外评估了正在发生小鼠胰岛自身免疫和人类T1D的T细胞中DHODH抑制诱导Treg的特征。为了剖析这些观察结果的功能相关性，我们在体内T1D临床前模型中测试了DHODH抑制对干扰自身免疫激活和疾病进展的影响。
我们发现，DHODH抑制在体外可增强Treg诱导，尤其是在免疫激活增强期间，并减少T细胞增殖。此外，维托鲁胺钙降低了两种小鼠模型中T1D的发病率。在细胞水平上，接受治疗的小鼠T细胞激活减少，同时Treg频率增加。
我们证明，通过新一代DHODH抑制来限制嘧啶从头合成是一种干扰自身免疫激活同时促进Treg生成的策略。
