EVidence of tolerance
Multiple sclerosis (MS) is an autoimmune disorder characterized by neuroinflammation and demyelination. Administration of myelin-specific self-antigens to induce tolerance has been shown to be effective in mouse models. However, identification of disease-relevant antigens is difficult. Now, Casella et al. showed that oligodendrocyte-derived extracellular vesicles (Ol-EVs) contained multiple myelin-related antigens and tested their potential therapeutic effects; in multiple rodent models of experimental autoimmune encephalomyelitis (EAE), Ol-EV administration restored immune tolerance and reduced disease pathophysiology. The results suggest that Ol-EVs might be an effective approach for MS.
Abstract
Autoimmune diseases such as multiple sclerosis (MS) develop because of failed peripheral immune tolerance for a specific self-antigen (Ag). Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven effective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. One such approach is intravenous tolerance induction by injecting a myelin Ag used for triggering EAE. However, the translation of this and similar experimental strategies into therapy for MS has been hampered by uncertainty regarding relevant myelin Ags in MS patients. To address this issue, we developed a therapeutic strategy that relies on oligodendrocyte (Ol)–derived extracellular vesicles (Ol-EVs), which naturally contain multiple myelin Ags. Intravenous Ol-EV injection reduced disease pathophysiology in a myelin Ag–dependent manner, both prophylactically and therapeutically, in several EAE models. The treatment was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive CD4+ T cells. Furthermore, we showed that human Ols also released EVs containing most relevant myelin Ags, providing a basis for their use in MS therapy. These findings introduce an approach for suppressing central nervous system (CNS) autoimmunity in a myelin Ag–specific manner, without the need to identify the target Ag.
