Reprogramming autoimmunity: inducing antigen-specific tolerance via apoptotic mimicry in an experimental model of...

Multiple sclerosis (MS) is an immune-mediated disorder characterized by demyelination, axonal damage, and neurodegeneration, leading to neurological disability in patients. It is considered a prototypic antigen-specific autoimmune disease, and therefore is a strong candidate for therapies aimed at restoring immune tolerance to self-antigens. However, the development of effective antigen-specific tolerization remains an important unmet medical need. In the present study, we administered phosphatidylserine (PS) liposomes, mimicking apoptotic bodies, containing a myelin antigen [35-55 myelin oligodendrocyte glycoprotein (MOG_35 - 55) peptide] in the MOG_35 - 55-induced experimental autoimmune encephalomyelitis (EAE), as a therapeutic strategy for the treatment of MS.

MOG PS liposomes or empty PS liposomes were administered in a single administration before or after the appearance of EAE neurological symptoms. Intraperitoneal, intranasal, intradermal and intravenous administration routes were used. For mechanistic studies, peripheral T and B cell subpopulations of treated EAE mice were studied by flow cytometry. In addition, EAE mice treated with MOG PS liposomes received blocking antibodies to deplete Treg, B cells, and immunomodulatory mediators IL-10 and TGF-β. The efficacy of the therapy was compared with daily administration of fingolimod.

We demonstrated the therapeutic efficacy of the MOG-loaded PS liposomes when administered intraperitoneally before onset, and the mechanism of action of MOG-loaded PS liposomes involved Treg and B cells, since blocking these populations and their related molecules IL-10 and TGF-β, abrogated the tolerogenic effect of the therapy. We also demonstrated the therapeutic efficacy of the MOG-loaded PS liposomes when administered intraperitoneally after appearance of EAE neurological signs. Alternative routes of administration such as intravenous and intradermal, which are more suited for translation in clinical trials, were found to be efficacious before and after appearance of EAE neurological signs. Intravenous administration of MOG-loaded PS liposomes in established EAE reduced dendritic cell activation, decreased inflammatory cytokine secretion, induced T cell exhaustion and expanded regulatory B cells (Breg) and CD39⁺CD4⁺FoxP3⁺ T cells.

Our findings indicate that antigen-specific therapy with PS liposomes mimicking apoptotic bodies downregulates the MOG-specific inflammatory immune response and expands Breg and Treg cells, offering a safe, versatile, and easily applicable approach that strongly supports its potential for near-future clinical translation in MS.