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

TY - JOUR

T1 - 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

AU - Sanchez-Guajardo, Vanesa

AU - Annibali, Ambra

AU - Jensen, Poul Henning

AU - Romero-Ramos, Marina

PY - 2013/7

Y1 - 2013/7

N2 - 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.

AB - 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.

KW - Animals

KW - Antigens, CD/metabolism

KW - Cell Count

KW - Corpus Striatum/metabolism

KW - Disease Models, Animal

KW - Disease Progression

KW - Epitope Mapping

KW - Female

KW - Genetic Vectors/physiology

KW - Glial Cell Line-Derived Neurotrophic Factor/metabolism

KW - Histocompatibility Antigens Class II/metabolism

KW - Humans

KW - Inclusion Bodies/metabolism

KW - Microglia/pathology

KW - Motor Activity/immunology

KW - Nerve Fibers/metabolism

KW - Parkinson Disease/immunology

KW - Rats

KW - Rats, Sprague-Dawley

KW - Substantia Nigra/immunology

KW - Vaccination/methods

KW - alpha-Synuclein/immunology

U2 - 10.1097/NEN.0b013e31829768d2

DO - 10.1097/NEN.0b013e31829768d2

M3 - Article

C2 - 23771222

SN - 0022-3069

VL - 72

SP - 624

EP - 645

JO - Journal of Neuropathology and Experimental Neurology

JF - Journal of Neuropathology and Experimental Neurology

IS - 7

ER -