Objective: Test the hypothesis that combining humoral and immunosuppressive cellular asyn immunization will enhance asyn clearance, and reduce inflammation and neuropathological symptoms in a human asyn tg animal model system.

Background: Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of alpha-synuclein (asyn; synucleinopathy) and currently no disease modifying treatments are available. Previous studies in transgenic (tg) mice have shown that active and passive immunization to asyn reduces asyn accumulation and disease symptoms.   It has been recently reported that the co-delivery of an antigen + Rapamycin (Rap) in nanoparticles induced antigen-specific T regulatory (Treg) cells.  We adapted this immunization strategy to asyn using the antigen-presenting cell targeting glucan particle (GP) vaccine delivery system.

Methods: Glucan Particles were loaded with recombinant full-length human-asyn (h-asyn), Rap or h-asyn + Rap. A macrophage cell line expressing LC3-GFP was used to demonstrate Rap delivery and induction of autophagy. PDGF-asyn tg and control non-tg mice were immunized with: Groups 1) GP alone, 2) GP + human h-asyn, 3) GP + Rap and 4) GP + Rap + h-asyn vaccines and analyzed by immunological, biochemical and neuropathological markers.

Results: Group 2 – GP + h-asyn or Group 4 – GP + Rap + h-asyn immunized mice showed strong total IgG, IgG1 and IgG2 anti-asyn titers, levels were slightly higher in the combined asyn + Rap group.  Asyn levels in the frontal cortex and hippocampus in Groups 2 and 4 asyn immunized mice were reduced between 30-50% when compared to control Groups 1 and 3 non-Tg immunized mice.  Asyn reduction in the combined asyn + Rap group was greater.  Combined immunotherapy in Group 4 – GP + Rap + h-asyn mice resulted in increased levels of CD25, FoxP3 and CD4 positive Treg cells and TGFb1, and reduced neuro-inflammation (Iba-1, GFAP, IL6, TNFalpha) by microglial and astroglial cells.

Conclusions: In vivo vaccination studies targeting alpha-synuclein support the hypothesis that immunization to generate Treg cells might enhance the effects of active immunotherapy for the treatment of synucleionopathies. Future work will focus on the asyn antigen specificity of induced Tregs and application to other neurodegenerative proteinopathy-mediated diseases.

Supported by grants from NIH grant AG18440

« Back to 2017 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/development-of-a-prototype-alpha-synuclein-vaccine-to-induce-t-regulatory-cells-for-the-treatment-of-synucleonopathy/