Abstract
BackgroundThe development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Aβ antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Aβ42 (Aβ1–11) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype.Methods and FindingsWe generated pMDC-3Aβ1–11-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3–4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Aβ antibody, which in turn inhibited accumulation of Aβ pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.ConclusionsData from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials.
Highlights
A critical aim in developing therapeutic interventions for Alzheimer’s Disease (AD) is the identification of suitable targets
We have engineered a DNA vaccine construct that encodes MDC fused in frame with three copies of the immunodominant self-B cell epitope of Ab42 (3Ab1–11), and foreign T helper (Th) cell epitope, PADRE [22]
To test the immunogenicity of our DNA epitope vaccine in vivo, both 3xTg-AD and C57/Bl6 mice of H2b immune haplotype were immunized with pMDC-3Ab1–11-PADRE (Figure 1D), and cellular and humoral immune responses were assessed
Summary
A critical aim in developing therapeutic interventions for Alzheimer’s Disease (AD) is the identification of suitable targets. It is estimated that there are currently about 18 million people worldwide with AD. The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Ab antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Ab42 (Ab1–11) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong antiinflammatory Th2 phenotype
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