title: α-Synuclein vaccination prevents the accumulation of parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model.
abstract: Human leukocyte antigen-DR induction and lymphocyte infiltrates in the brains of patients with Parkinson disease (PD) and the presence in serum of α-synuclein (α-syn)-specific antibodies suggest that the peripheral immune system may have an active role in the progression of PD. We designed a vaccination strategy to attempt to control these processes and mediate protection against disease progression in a rat PD model. Using a recombinant adeno-associated viral vector, we unilaterally overexpressed human α-syn in the rat substantia nigra to induce a progressive neuropathologic process. Prior to stereotactic delivery of the viral vector, animals were vaccinated with recombinant α-syn (asyn). This resulted in a high-titer anti-α-syn antibody response on α-syn overexpression; the accumulation of CD4-positive, MHC II-positive ramified microglia in the substantia nigra; long-lasting infiltration of CD4-positive, Foxp3-positive cells throughout the nigrostriatal system; and fewer pathologic aggregates in the striatum versus control animals that had received a mock vaccine. A long-term increase in GDNF levels in the striatum and IgG deposition in α-syn-overexpressing cells and neurites in the substantia nigra were also observed. Together, these results suggest that a protective vaccination strategy results in induction of regulatory T cells and distinctly activated microglia, and that this can induce immune tolerance against α-syn.
authors.affiliation: CNS Disease Modeling Group, Department of Biomedicine, Aarhus University, Aarhus C, Denmark. vsg@biokemi.au.dk
authors.forename: Vanesa
authors.initials: V
authors.lastname: Sanchez-Guajardo
authors.forename: Ambra
authors.initials: A
authors.lastname: Annibali
authors.forename: Poul Henning
authors.initials: PH
authors.lastname: Jensen
authors.forename: Marina
authors.initials: M
authors.lastname: Romero-Ramos
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D018604:Epitope Mapping; D005260:Female; D005822:Genetic Vectors / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D017628:Microglia / Q000473:pathology; D009043:Motor Activity / Q000276:immunology; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000276:immunology* / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014611:Vaccination / Q000379:methods*; D051844:alpha-Synuclein / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000949:Histocompatibility Antigens Class II; C497604:SNCA protein, human; D051844:alpha-Synuclein