posted on 2021-11-29, 22:29authored byKin Man Au, Roland Tisch, Andrew Z. Wang
Type
1 diabetes mellitus (T1DM) is an autoimmune disease caused
by autoreactive T cells targeting the insulin-producing beta (β)
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 β cells in situ to induce β-cell-specific tolerance. We hypothesized
that β-cell-targeted Ac4ManNAz-encapsulated nanoparticles
deliver and establish β 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
β cells. Using nonobese diabetic (NOD) mice, we demonstrated
that our strategy effectively and selectively conjugates PD-L1 onto
β cells through bioorthogonal stain-promoted azide–alkyne
cycloaddition. We also showed that the in vivo functionalized
β 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.