Cover Story Current Issue
Despite intensive drug development efforts and public health initiatives, obesity is increasing in incidence and predicted to affect over 50% of all adults worldwide by 2035. Being chronically overweight increases the risk of serious disease co-morbidities that, in turn, increase mortality and healthcare costs. Behavioral approaches to combat obesity, such as diet and exercise, rarely produce lasting weight loss commonly due to compensatory hyperphagia and hypometabolism. These limitations have stimulated interest in pharmacotherapies that target gut-derived peptide hormones involved in the regulation of energy homeostasis, such as PYY, GIP, CCK, and GLP-1. These peptides are secreted by different enteroendocrine cells distributed throughout the intestine in response to food intake, subsequently enhancing satiation signaling and ultimately promotes meal termination. However, a major challenge of FDA-approved and experimental weight-loss medications that target GI-derived satiation signals is the frequent occurrence of nausea and vomiting.
Current Issue
Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes
Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes
Objective
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.
Results
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.
Articles in Press
Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes
Inhibition of pyrimidine de novo synthesis fosters Treg cells and reduces diabetes development in models of Type 1 Diabetes
Objective
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.
Results
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.
SAVE THE DATE!
13th
Helmholtz Diabetes Conference
Munich, 21-23. Sep 2026
2024 impact factor: 6.6
You are what you eat
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