Beta cell-targeted PD-1 agonist inhibits cell-mediated autoimmunity in pancreas tissue slices.

Abstract

This research evaluates a therapeutic approach based on tissue-targeted immunomodulation with a potential broad application to treat autoimmune diseases including type 1 diabetes (T1D). We generated a bispecific immune agonist that binds beta cells and suppresses autoreactive T cells. These bispecific molecules called immune modulating monoclonal-T cell receptor (TCR) against autoimmune disease (ImmTAAI), consist of a human-specific TCR-targeting domain fused with a programmed death-1 agonist. We used live pancreas slices to demonstrate targeting of ImmTAAI molecules to preproinsulin peptide-HLA-A2 complexes on human beta cells. ImmTAAI molecules protected beta cells from T cell killing by increasing T cell motility and inhibiting effector molecule and cytokine secretion. ImmTAAI treatment also increased the motility of islet-infiltrating T cells in slices from a donor with recent-onset T1D and preserved insulin secretion in slices cocultured with T cell avatars transduced with diabetogenic TCRs. These data demonstrate that ImmTAAI molecules have the potential to limit T cell activity locally, making this an attractive platform to elicit targeted immunoregulation in T1D.