Pre-clinical evaluation of TYK2 inhibitors for human beta cell protection in type 1 diabetes
- Coomans de Brachène, Alexandra
- Castela, Angela
- Op de Beeck, Anne
- Mirmira, Raghavendra G
- Marselli, Lorella
- Marchetti, Piero
- Masse, Craig
- Miao, Wenyan
- Leit, Silvana
- Evans-Molina, Carmella
- Eizirik, Decio L
Publication date
January 2020
DOIAbstract
Type 1 diabetes (T1D) is a chronic autoimmune disease leading to progressive loss of pancreatic beta cells. Interferon (IFN)-α plays a critical role in the crosstalk between pancreatic beta cells and the immune system in early insulitis. In human beta cells IFNα signals through JAK1 and TYK2, leading to endoplasmic reticulum stress, inflammation and HLA class I overexpression. IFNα, acting synergistically with IL-1β, 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 IFNα
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