Nanoparticles targeting liver sinusoidal endothelial cells improve tolerance to vector and transgene antigens through tolerance spreading
Nanoparticles targeting liver sinusoidal endothelial cells improve tolerance to vector and transgene antigens through tolerance spreading
Journal: Molecular Therapy
Authors:
Summary
Liver sinusoidal endothelial cells (LSECs) naturally cross-present antigens and induce T cell tolerance. Targeting LSECs with peptide-coupled nanoparticles offers an efficient strategy to induce antigen-specific immune tolerance. Previous preclinical and clinical studies have shown that peptide-coupled nanoparticles can effectively inhibit T cell responses to the selected cognate peptide epitopes. However, clinical situations such as viral-vector-mediated gene therapy would benefit from simultaneous tolerance induction to multiple epitopes/antigens, posing a significant challenge. In this study, we used mouse models of adeno-associated virus (AAV)-mediated gene transfer to assess the in vivo effects of peptide-loaded nanoparticles designed to tolerize immune responses to transgene- or/and capsid-derived epitopes. We report here for the first time that LSEC-targeting nanoparticles coupled to a single peptide epitope promoted extension of tolerance to multiple relevant epitopes/antigens and simultaneously tolerized both CD4+ and CD8+ T cell responses. This tolerance spreading, which we termed “Tspread,” remained specific to the transgene- and capsid-derived antigens conveyed by the administered AAV vector and did not impair immune responses to an unrelated vaccine antigen. These findings delineate a novel LSEC-mediated tolerance spreading with important clinical implications for viral-vector gene therapy, where tolerance to multiple epitopes/antigens is essential for long-term expression of therapeutic genes.