Subcutaneous inverse vaccination with PLGA particles loaded with a MOG peptide and IL-10 decreases the severity of experimental autoimmune encephalomyelitis |
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| Authors: | Giuseppe Cappellano,Abiy Demeke Woldetsadik,Elisabetta Orilieri,Yogesh Shivakumar,Manuela Rizzi,Fabio Carniato,Casimiro Luca Gigliotti,Elena Boggio,Nausicaa Clemente,Cristoforo Comi,Chiara Dianzani,Renzo Boldorini,Annalisa Chiocchetti,Filippo Renò ,Umberto Dianzani |
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| Affiliation: | 1. IRCAD and Department of Health Sciences, “A. Avogadro”, University of Eastern Piedmont “A. Avogadro”, via Solaroli 17, Novara, 28100, Italy;2. IRCAD and Department of Translational Medicine, Section of Neurology, “A. Avogadro”, University of Eastern Piedmont “A. Avogadro”, via Solaroli 17, Novara, 28100, Italy;3. Innovative Research Laboratory for Wound Healing, Department of Health Sciences, University of Eastern Piedmont “A. Avogadro”, via Solaroli 17, 28100 Novara, Italy;4. Department of Science and Technology, University of Eastern Piedmont “A. Avogadro”, viale Teresa Michel 11, 15121 Italy;5. Department of Drug Science and Technology, University of Turin, via Pietro Giuria 9, 10125 Torino, Italy |
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| 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. |
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| Keywords: | BCA, bicinchoninic acid CHOs, Chinese hamster ovary cells CNS, central nervous system CTL, cytotoxic T lymphocytes DCM, dichloromethane DLS, dynamic light scattering EAE, experimental autoimmune encephalomyelitis FDA, food and drug administration H& E, hematoxylin& eosin IFN, interferon IL, interleukin LPS, lipopolysaccharide MCF-7, human breast adenocarcinoma cell line MBP, myelin basic protein MFI-R, mean fluorescence intensity ratio MRI, magnetic resonance imaging MOG, myelin oligodendrocyte glycoprotein MS, multiple sclerosis MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Ni-NTA, nickel-nitrilotriacetic agarose NIRF, near-infrared fluorescence NK, natural killer NP, nano/microparticles OD, optical density PBMCs, peripheral blood mononuclear cells PBS, phosphate-buffered saline PDI, polydispersity index PLGA, polymeric biodegradable lactic&ndash glycolic acid PLP, proteolipid protein r, recombinant PVA, poly/vinyl alcohol RR, relapsing remitting form RT, room temperature s.c., subcutaneous injections SEM, scanning electron microscope SE, standard error TH, T helper TEFF, effector T TGF, transforming growth factor TNF, Tumor Necrosis Factor TREG, regulatory T |
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