Astrocyte-derived extracellular vesicles as antigen-specific therapy for neuromyelitis optica spectrum disorder in the mouse model

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by Th17 cell responses and serum antibodies against the water channel aquaporin-4 (AQP4) on astrocytes. To avoid systemic immunosuppression by current therapies, an approach is to induce antigen (Ag)-specific tolerance by injecting an AQP4 epitope used to trigger the disease (e.g., AQP4201-220). The prerequisite for Ag-specific therapy is identification of the target Ag; however, dozens of epitopes of AQP4 and certain non-AQP4 astrocyte Ags have been identified as auto-Ags in NMOSD patients and in animal models. This uncertainty regarding relevant astrocyte Ags would hinder the translation of this and similar experimental strategies into Ag-specific therapy for NMOSD patients. In our study, we developed a therapeutic approach for an experimental NMOSD (eNMOSD) mouse model that relies on astrocyte-derived extracellular vesicles (AST-EVs), which theoretically contain all astrocyte Ags. Intravenous injection of AST-EVs mitigates disease progression in an AQP-4 Ag-dependent manner in the eNMOSD model with ongoing disease. AST-EVs suppressed inflammation by decreasing immune cell infiltration of the CNS, inducing T cell apoptosis, and increasing the frequency of regulatory T cells and IL-35-producing B cells. Furthermore, we defined that IFN-{gamma} is crucial for successful i.v. tolerance induction by AST-EVs in eNMOSD. These novel findings represent a pioneering and considerable step toward a new therapeutic approach for NMOSD.