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

• DOI: 10.1097/nen.0b013e31829768d2
• Publication Date: 2013-06-14T05:58:11Z
• Authors: Vanesa Sanchez-Gu...; Ambra Annibali; Poul Henning Jensen; Marina Romero-Ramos
• Keywords: Inclusion Bodies; Genetic Vectors; Histocompatibility Antigens Class II; Cell Count; Parkinson Disease; Motor Activity; Corpus Striatum; Rats; 3. Good health; Rats, Sprague-Dawley; Substantia Nigra; Disease Models, Animal; 03 medical and health sciences; Nerve Fibers; 0302 clinical medicine; Antigens, CD; Disease Progression; Animals; Humans; Female; Glial Cell Line-Derived Neurotrophic Factor; Microglia; Epitope Mapping

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.