A curious feature of type I diabetes (T1D) is that, while the proteins that the immune system targets are broadly expressed in beta cells, inflammation of insulin-producing cells (insulitis) is patchy and damage develops gradually. In stage 1 or 2 T1D, prior to the onset of clinically evidence disease, the majority of insulin-producing cells are spared. Following the onset of T1D, and for many years after diagnosis, most individuals still have residual uninflamed and functional beta cells. These findings are suggestive of immune mechanisms that are active in the vicinity of unaffected islets that protects them from autoreactive damage, but these are not well understood. They are of significant interest however, as a critical need in type I diabetes (T1D) is to develop therapies that can prevent progression of pre-clinical disease to overt diabetes or protect residual beta cell function. We hypothesize that, if we can identify the cellular and molecular mechanisms that constrain excessive auto-reactive responses in the pancreas, we can use this knowledge to develop therapies that enhance them.
To understand these mechanisms we propose two complementary approaches. Firstly we will use single nuclear RNA sequencing (Flex Gene Expression) to understand the cellular composition and expression profile of the pancreas at different stages of disease. Secondly we will apply spatial transcriptomics to determine how these vary in relation to their physical location and, in particular, how they vary between inflamed and unaffected islets within the same pancreas.