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

Kin Man Au, Roland Tisch, Andrew Z. Wang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)19990-20002
Number of pages13
JournalACS Nano
Volume15
Issue number12
DOIs
StatePublished - Dec 28 2021

Keywords

  • immune checkpoints
  • immunotolerance
  • pretargeting
  • stain-promoted azide-alkyne cycloaddition
  • type 1 diabetes mellitus

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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