Abstract Text: Type 1 Diabetes (T1D) is an autoimmune disease characterized by the T cell mediated destruction of insulin-producing β-cells. Antigen-specific Tregs are efficient regulators in suppressing autoimmunity, making them attractive targets for tolerogenic therapy. However, it remains unknown how to efficiently induce antigen-specific Tregs in vivo. Here, we report the development of a novel synthetic high-density-lipoprotein-based nanodiscs (ND) for the delivery of autoantigens and induction of immune tolerance in mouse T1D models.
ND was prepared by lyophilization approach [1]. Chromogranin A-derived mimetopes (p31 and 2.5mi) were incorporated onto ND. By using BDC2.5 and NY8.3 adoptive transfer models of T1D, we optimized the dosing regimen and improved the efficacy in protecting against disease.
Subcutaneous treatments with p31-ND completely prevented diabetes in NOD.SCID mice transferred with preactivated BDC2.5 splenocytes. In a BDC2.5 + NY8.3 co-transfer model, treatment with p31-ND delayed the disease progression from 8 days to an average of 4 weeks, indicating bystander suppression. Mechanistically, one single dose of 2.5mi-ND induced 2.5mi-specific T cells that exhibited anergic phenotypes. In NOD.SCID mice, p31-ND treatment after co-transfer of BDC2.5 CD4 T cells and NY8.3 CD8 T cells enriched antigen-specific anergic CD4 T cells and Foxp3+Treg cells in the pancreas and prevented CD8 T cell activation and infiltration.
Collectively, these results show that ND induces antigen-specific Tregs that dampen ongoing autoimmunity, potentially through recognizing the same tissue-specific self-antigens or through bystander suppression. The novel antigen-specific therapy may have implications for development of immune modulating treatment for T1D patients.
