Journal Article Ahead of print
PubMed: 41821311 DOI: 10.1016/j.ymthe.2026.03.009
Nanoparticles targeting liver sinusoidal endothelial cells improve tolerance to vector and transgene antigens through tolerance spreading.
Mol Ther
Authors: Romain Hardet, Shu-Hung Wang, Sandrine Delignat, Marine Blandin, Reinaldo Digigow, Cornelia Gottwick, Markus Heine, Lígia Margarida Marques Mesquita, Marco Fanzutti, Anna-Lisa Vocaturo, Disha Mungalpara, Olivier Boyer, Sébastien Lacroix- Desmazes, Sabine Fleischer, Sahil Adriouch
Affiliations
- Univ Rouen Normandie, INSERM, Normandie Univ, PANTHER UMR 1234, F-76000 Rouen, France.
- Topas Therapeutics GmbH, Hamburg, Germany.
- Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université de Paris, F-75006 Paris, France.
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
- Department of Biochemistry and Molecular Cell Biology (N30), University Medical Clinic Hamburg-Eppendorf, Hamburg, Germany.
- Univ Rouen Normandie, INSERM, Normandie Univ, PANTHER UMR 1234, F-76000 Rouen, France; CHU de Rouen, Department of Immunology and Biotherapy, Rouen, France.
- Topas Therapeutics GmbH, Hamburg, Germany.
- Univ Rouen Normandie, INSERM, Normandie Univ, PANTHER UMR 1234, F-76000 Rouen, France.
Abstract
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 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 one 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.
MeSH
Cells, Genes, Epitopes, Nanoparticles, Transgenes, Liver, Capsid, Immunity, Endothelial Cells, Therapeutics