title: Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis.
abstract: "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)35-55 autoantigen and recombinant (r) IL-10 to inverse vaccinate mice with EAE. In vitro experiments showed that upon encapsulation in PLGA-NP, both MOG35-55 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 MOG35-55 and rIL-10 significantly ameliorated the course of EAE induced with MOG35-55 in C57BL/6 mice. Moreover, they decreased the histopathologic lesions in the central nervous tissue and the secretion of IL-17 and interferon (IFN)-γ induced by MOG35-55 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.
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy. Electronic address: giuseppe.cappellano@med.unipmn.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cappellano
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Abiy Demeke
authors.initials: AD
authors.lastname: Woldetsadik
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Shivakumar
authors.affiliation: Innovative Research Laboratory for Wound Healing, Department of Health Sciences, University of Eastern Piedmont "A. Avogadro", via Solaroli 17, 28100 Novara, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rizzi
authors.affiliation: Department of Science and Technology, University of Eastern Piedmont "A. Avogadro", viale Teresa Michel 11, 15121 Alessandria, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Carniato
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Casimiro Luca
authors.initials: CL
authors.lastname: Gigliotti
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Clemente
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Comi
authors.affiliation: Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dianzani
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Boldorini
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
authors.affiliation: Innovative Research Laboratory for Wound Healing, Department of Health Sciences, University of Eastern Piedmont "A. Avogadro", via Solaroli 17, 28100 Novara, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Renò
authors.affiliation: dIRCAD and Department of Translational Medicine, Section of Neurology, "A. Avogadro", University of Eastern Piedmont "A. Avogadro", via Solaroli 17, Novara, 28100, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000276:immunology; D020381:Interleukin-17 / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage*; D061986:MCF-7 Cells; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage*; D053758:Nanoparticles / Q000008:administration & dosage; D011100:Polyglycolic Acid / Q000008:administration & dosage*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011994:Recombinant Proteins / Q000008:administration & dosage; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination
chemical_list: D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D011994:Recombinant Proteins; D016753:Interleukin-10; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007371:Interferon-gamma
keywords: Interleukin-10; PLGA; T(REG); Tolerogenic vaccine