Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

Background Tyrosine protein-kinase 2 (TYK2) mediates inflammatory signalling through multiple cytokines, including interferon-alpha (IFN alpha), 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. Methods We evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D, including human beta cells, cadaveric islets, iPSC-derived islets, and mouse models. Findings In vitro studies showed that TYK2is prevented IFN alpha-induced beta cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of beta cells with TYK2i prevented IFN alpha-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 beta 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. Interpretation These 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. Copyright Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).