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

• Published in: ACS nano 2021-12, Vol.15 (12), p.19990-20002
• Main Authors: Au, Kin Man, Tisch, Roland, Wang, Andrew Z
• Format: Article
• Language: English
• Subjects: Alkynes; Animals; Benzyl Compounds; Bioengineering; Diabetes Mellitus, Type 1 - drug therapy; Humans; Insulin-Secreting Cells; Ligands; Mice; Mice, Inbred NOD
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.1c07538

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.