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., AQP4(201-220)). 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-γ 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.