Pre-clinical evaluation of TYK2 inhibitors for human beta cell protection in type 1 diabetes.

Aim Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)-alpha plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFN alpha signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFN alpha, acting synergistically with IL-1 beta, induces apoptosis. Polymorphisms in TYK2 that decrease its activity are associated with protection against T1D, and we hypothesized that pharmacological inhibitors that specifically target TYK2 could protect human beta cells against the deleterious effects of IFN alpha. Materials and Methods Two TYK2 inhibitors provided by Nimbus Lakshmi were tested in human insulin-producing EndoC-beta H1 cells and human islets to evaluate their effect on IFN alpha signalling, beta-cell function and susceptibility to viral infection using RT-qPCR, western blot, immunofluorescence, ELISA and nuclear dyes. Results The two TYK2 inhibitors tested prevented IFN alpha-induced human beta-cell gene expression in a dose-dependent manner. They also protected human islets against IFN alpha + IL-1 beta-induced apoptosis. Importantly, these inhibitors did not modify beta-cell function or their survival following infection with the potential diabetogenic coxsackieviruses CVB1 and CVB5. Conclusions The two TYK2 inhibitors tested inhibit the IFN alpha signalling pathway in human beta cells, decreasing its pro-inflammatory and pro-apoptotic effects without sensitizing the cells to viral infection. The preclinical findings could pave the way for future clinical trials with TYK2 inhibitors for the prevention and treatment of type 1 diabetes.