Reducing AD-Like Pathology in 3xTg-AD Mouse Model by DNA Epitope Vaccine — A Novel Immunotherapeutic Strategy

BACKGROUND: The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Abeta 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 Abeta(42) (Abeta(1-11)) , 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 FINDINGS: We generated pMDC-3Abeta(1-11)-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-Abeta antibody, which in turn inhibited accumulation of Abeta 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. CONCLUSIONS: Data 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

Reducing AD-Like Pathology in 3xTg-AD Mouse Model by DNA Epitope Vaccine -- A Novel Immunotherapeutic Strategy

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

Health assessment of future PM_2.5 exposures from indoor, outdoor, and secondhand tobacco smoke concentrations under alternative policy pathways in Ulaanbaatar, Mongolia

<div><p>Introduction</p><p>Winter air pollution in Ulaanbaatar, Mongolia is among the worst in the world. The health impacts of policy decisions affecting air pollution exposures in Ulaanbaatar were modeled and evaluated under business as usual and two more-strict alternative emissions pathways through 2024. Previous studies have relied on either outdoor or indoor concentrations to assesses the health risks of air pollution, but the burden is really a function of total exposure. This study combined projections of indoor and outdoor concentrations of PM_2.5 with population time-activity estimates to develop trajectories of total age-specific PM_2.5 exposure for the Ulaanbaatar population. Indoor PM_2.5 contributions from secondhand tobacco smoke (SHS) were estimated in order to fill out total exposures, and changes in population and background disease were modeled. The health impacts were derived using integrated exposure-response curves from the Global Burden of Disease Study.</p><p>Results</p><p>Annual average population-weighted PM_2.5 exposures at baseline (2014) were estimated at 59 μg/m³. These were dominated by exposures occurring indoors, influenced considerably by infiltrated outdoor pollution. Under current control policies, exposures increased slightly to 60 μg/m³ by 2024; under moderate emissions reductions and under a switch to clean technologies, exposures were reduced from baseline levels by 45% and 80%, respectively. The moderate improvement pathway decreased per capita annual disability-adjusted life year (DALY) and death burdens by approximately 40%. A switch to clean fuels decreased per capita annual DALY and death burdens by about 85% by 2024 with the relative SHS contribution increasing substantially.</p><p>Conclusion</p><p>This study demonstrates a way to combine estimated changes in total exposure, background disease and population levels, and exposure-response functions to project the health impacts of alternative policy pathways. The resulting burden analysis highlights the need for aggressive action, including the elimination of residential coal burning and the reduction of current smoking rates.</p></div

Estimates of age-specific city-wide population and household number by home type, and estimated household size.

<p>Estimates of age-specific city-wide population and household number by home type, and estimated household size.</p

High-level flow chart of the general exposure and disease analysis approach.

<p>Annual average exposures were estimated for population sub-groups in 2014 and in 2024 under BAU and two alternative policy pathways from outdoor and indoor concentration models and time activity estimates using the approach summarized above. These exposures were applied to disease-specific exposure response curves to produce estimates of population attributable fraction (PAF) which were applied to background disease rates to quantify attributable disease burden. Detailed data descriptions and methods–including how interim year (2015–2023) disease burdens were calculated–are included in the manuscript and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0186834#pone.0186834.s001" target="_blank">S1 Text</a>.</p