Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice

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.

Neural stem cells traffic functional mitochondria via extracellular vesicles

“…While it is not possible to fully dissect the functional impact of free or EV-encapsulated mitochondria separately, our data strongly suggest that mitochondria in EV preparations, and the CD63 + EV fraction, are indispensable for the in vivo therapeutic effect. In addition to classical cellular grafts [37], these new data further support the use of EV-based acellular therapies in regenerative neuroimmunology [70].…”

Potential Roles of Extracellular Vesicles as Biomarkers and a Novel Treatment Approach in Multiple Sclerosis

“…This EV-based vaccine was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive CD4+ T cells. These findings introduce an approach to suppressing CNS autoimmunity in a myelin antigen-specific manner, without the need to identify the target antigens [88].…”

“…However, the relevant self-myelin antigen in MS remains speculative, with the possibility that these antigens differ among patients and over time in the same patient. It has been shown that PLP is mainly present in small EVs, which are enriched in exosomes, whereas MBP and MOG are mainly present in large EVs, specifically the fraction enriched in microvesicles [88]. Given that EVs include exosomes and microvesicles, Casella et al used total EVs from oligodendrocytes (which naturally contain most of the relevant myelin antigens) as an EV-based vaccine in various experimental animal models of MS.…”

Extracellular Vesicles as Pro- and Anti-inflammatory Mediators, Biomarkers and Potential Therapeutic Agents in Multiple Sclerosis

“…Recently the same group have shown that, naturally derived EVs from oligodendrocytes culture contains myelin antigens and transfer of this EVs reduce EAE pathophysiology in a myelin antigen-dependent manner in EAE models [77]. Interestingly EVs derived from MSC protects oligodendrocytes from DNA damage and EVs from MSC co-cultured with microglia helps the myelin repair by recruiting oligodendrocyte precursor (OPC) in demyelinated regions [78,79].…”