Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis

Abstract

a b s t r a c t "Inverse vaccination" refers to antigen-specific tolerogenic immunization treatments that are capable of inhibiting autoimmune responses. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), initial trials using purified myelin antigens required repeated injections because of the rapid clearance of the antigens. This problem has been overcome by DNA-based vaccines encoding for myelin autoantigens alone or in combination with "adjuvant" molecules, such as interleukin (IL)-4 or IL-10, that support regulatory immune responses. Phase I and II clinical trials with myelin basic protein (MBP)-based DNA vaccines showed positive results in reducing magnetic resonance imaging (MRI)-measured lesions and inducing tolerance to myelin antigens in subsets of MS patients. However, DNA vaccination has potential risks that limit its use in humans. An alternative approach could be the use of protein-based inverse vaccines loaded in polymeric biodegradable lactic-glycolic acid (PLGA) nano/microparticles (NP) to obtain the sustained release of antigens and regulatory adjuvants. The aim of this work was to test the effectiveness of PLGA-NP loaded with the myelin oligodendrocyte glycoprotein (MOG) autoantigen and recombinant (r) IL-10 to inverse vaccinate mice with EAE. In vitro experiments showed that upon encapsulation in PLGA-NP, both MOG 35-55 and rIL-10 were released for several weeks into the supernatant. PLGA-NP did not display cytotoxic or proinflammatory activity and were partially endocytosed by phagocytes. In vivo experiments showed that subcutaneous prophylactic and therapeutic inverse vaccination with PLGA-NP loaded with MOG 35-55 and rIL-10 significantly ameliorated the course of EAE induced with MOG 35-55 in C57BL/6 mice. Moreover, they decreased the histopathologic lesions in the central nervous tissue and the secretion of IL-17 and interferon (IFN)-␥ induced by MOG in splenic T cells in vitro. These data suggest that subcutaneous PLGA-NP-based inverse vaccination may be an effective tool to treat autoimmune diseases.

An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis

“…The dMP-MOG 35-55 approach is based on delivery of specific antigens and tolerogenic factors encapsulated in PLGA MPs for controlled release in a local microenvironment. Similar approaches using PLGA nanoparticles and EAE-specific antigens with or without tolerogenic factors have been investigated [51, 76-79]. However, the present dMP-MOG 35-55 treatment, administered subcutaneously, suppressed EAE, whereas several previously reported PLGA-based nanoparticle formulations relied on intravenous administration [51, 76] or required intra-lymph node injection [78].…”

“…Nanoparticle formulations that have prevented EAE have included highly immunosuppressive drugs such as rapamycin [77], which has demonstrated toxicity for other cell types including pancreatic β-cells [82]. The present dMP-MOG 35-55 therapy mitigates EAE without highly immunosuppressive drugs, simultaneously providing more efficacious therapeutic aid compared to other PLGA vaccines, such as IL-10 nanoparticles [79]. IL-10 nanoparticles in combination with MOG 35-55 peptide were previously used in prophylactic as well as therapeutic regimens and showed some decrease in EAE severity [79], however more modest than in our treatments.…”

Engineered erythrocytes covalently linked to antigenic peptides can protect against autoimmune disease

“…Cell types other than the intended phagocytes may acquire the antigen, leading to uncertain outcomes (9,45,46). When using nanoparticles/microparticles as a vehicle for the delivery of autoantigens (46)(47)(48)(49), one must consider delivery to many different sites depending on size and other biophysical properties of these preparations.…”

Application of nanomedicine for crossing the blood–brain barrier: Theranostic opportunities in multiple sclerosis

“…Furthermore, administration of proteolipid protein (PLP)-conjugated PLGA NP to EAE mice could effectively inhibit disease induction (Eaton et al 2013). Similarly, vaccination of EAE mice with PLGA-NP loaded with the MOG35-55 autoantigen and recombinant IL-10 was associated with ameliorating effects (Cappellano et al 2014).…”