ArticleEBioMedicine2025
Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice.
Article in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed.
- Shared non-HLA genetic architecture across diverse ancestries links insulin secretion and resistance to type 1 diabetes.Diabetologia · 2026Article
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- Beta cell microRNAs function as molecular hubs of type 1 diabetes pathogenesis and as biomarkers of diabetes risk.Diabetologia · 2026Article
- A mitochondrial ROS-dependent antiviral response promotes β cell resilience and is diminished in donors with type 1 diabetes.Science translational medicine · 2026Article
- New and emerging therapies in type 1 diabetes mellitus.The Journal of clinical investigation · 2026Review
- How Genomic and Structural Context Could Shape JAK-STAT Variant Pathogenicity.Twin research and human genetics : the official journal of the International Society for Twin Studies · 2026Article
- Stress-driven remodeling of antigen presentation and chemokine signaling in pancreatic β-cells: implications for type 1 diabetes.Frontiers in immunology · 2026Review
- Neoepitopes at the crossroads of immunometabolism: metabolic remodeling of antigen presentation in type 1 diabetes.Frontiers in immunology · 2026Review
- Significance of the tyrosine kinase 2 gene in both type 1 and type 2 diabetes.BMJ open diabetes research & care · 2025Article
- TYK2 inhibition enhances Treg differentiation and function while preventing Th1 and Th17 differentiation.Cell reports. Medicine · 2025Article
- Pharmacotherapeutic strategies to promote regulatory T cell function in autoimmunity.Current opinion in immunology · 2025Review
- IFN-α Induces Heterogenous ROS Production in Human β-Cells.bioRxiv : the preprint server for biology · 2025Article
- Janus kinase and signal transducer and activator of transcription inhibitors in type 1 diabetes and immune checkpoint-related diabetes: current status and future perspectives.Frontiers in immunology · 2025Review
- The perfect storm: unraveling the interplay of genetic predisposition and viral triggers in type 1 diabetes pathogenesis.Frontiers in endocrinology · 2025Review
- Inhibiting Tyrosine Kinase 2 Ameliorates Antiphospholipid Syndrome Nephropathy.Mediators of inflammation · 2024Article
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Abstract
backgroundTyrosine protein-kinase 2 (TYK2) mediates inflammatory signalling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. TYK2 missense mutations protect against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in other autoimmune conditions.
methodsWe evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D, including human β cells, cadaveric islets, iPSC-derived islets, and mouse models.
findingsIn vitro studies showed that TYK2is prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with TYK2i prevented IFNα-induced antigenic peptide presentation and alloreactive and autoreactive T cell degranulation. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP and NOD mice) reduced systemic and tissue-localised inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes, and spleen highlighted a role for TYK2 inhibition in modulating signalling pathways associated with inflammation, translational control, stress signalling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues.
interpretationThese findings indicate that TYK2i has beneficial effects on both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2is in human T1D.
fundingThis work was supported by the National Institutes of Health (NIH), Veteran Affairs (VA), Breakthrough T1D, and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, and the George and Frances Ball Foundation.
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