In Vivo Bioengineering of Beta Cells with Immune Checkpoint Ligand as a Treatment for Early-Onset Type 1 Diabetes Mellitus

摘要

Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by autoreactive T cells targeting the insulin-producing beta (beta) cells. Despite advances in insulin therapy, T1DM still leads to high morbidity and mortality in patients. A key focus of T1DM research has been to identify strategies that re-establish self-tolerance and suppress ongoing autoimmunity. Here, we describe a strategy that utilizes pretargeting and glycochemistry to bioengineer beta cells in situ to induce beta-cell-specific tolerance. We hypothesized that beta-celltargeted Ac(4)ManNAz-encapsulated nanoparticles deliver and establish beta cells with high levels of surface reactive azide groups. We further theorized that administration of a dibenzylcyclooctyne (DBCO)-functionalized programmed death-ligand 1 immunoglobulin fusion protein (PD-L1-Ig) can be readily conjugated to the surface of native beta cells. Using nonobese diabetic (NOD) mice, we demonstrated that our strategy effectively and selectively conjugates PD-L1 onto beta cells through bioorthogonal stain-promoted azide-alkyne cycloaddition. We also showed that the in vivo functionalized beta cells simultaneously present islet-specific antigen and PD-L1 to the engaged T cells, reversing early onset T1DM by reducing IFN-gamma expressing cytotoxic toxic T cells and inducing antigen-specific tolerance.