Abstract
The human pancreas, like almost all organs in the human body, is immunologically tolerated despite the presence of innate and adaptive immune cells that promptly mediate protective immune responses against pathogens in situ. The PD-1/PD-L1 inhibitory pathway seems to play a key role in the maintenance of immune tolerance systemically and within the pancreatic tissue. Tissue resident memory T cells (TRM), T regulatory cells (Treg), macrophages and even β cells exhibit PD-1 or PD-L1 expression that contributes in controlling pancreatic immune homeostasis and tolerance. Dysregulation of the PD-1/PD-L1 axis as shown by animal studies and our recent experience with checkpoint inhibitory blockade in humans can lead to immune dysfunctions leading to chronic inflammatory disease and to type 1 diabetes (T1D) in genetically susceptible individuals. In this review, we discuss the role of the PD-1/PD-L1 axis in pancreatic tissue homeostasis and tolerance, speculate how genetic and environmental factors can regulate the PD-1/PD-L1 pathway, and discuss PD-1/PD-L1-based therapeutic approaches for pancreatic islet transplantation and T1D treatment.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease mediated by T-cell destruction of the insulinproducing β-cells in the pancreatic islets of Langerhans [1]
Recent evidence indicates that the PD1/PD-L1 pathway is fundamental to prevent autoimmune diabetes so that, in some patients undergoing treatment with ICI, blocking this inhibitory pathway is sufficient to unleash islet-reactive T cells and trigger T1D
The important therapeutic implication of those findings is that restoring the Programmed death 1 (PD-1)/PDL1 function could represent a valid strategy to treat T1D at different stages: to counter-regulate β cell autoimmunity and prevent T1D in individuals genetically at-risk or autoantibodies positive (Stage 1/2), to promote immune tolerance and preserve residual β cell mass in new onset T1D patients (Stage 3) and, to reduce alloreactive responses and favor survival of transplanted islets in T1D patients with established disease (Stage 4)
Summary
Type 1 diabetes (T1D) is an autoimmune disease mediated by T-cell destruction of the insulinproducing β-cells in the pancreatic islets of Langerhans [1].
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