Multiple Approaches to Abeta Vaccination in Animal Models

描述(由申请人提供)：Aβ免疫疗法作为一种有前景的降低AD患者中枢神经系统中Aβ水平的方法，已受到相当大的关注。然而，第一项临床试验是1792年，当Abeta42免疫者的一部分人在中枢神经系统出现不良事件时，第一项临床试验被叫停，试验数据表明，接受疫苗的患者中应答者比例较低，滴度普遍较低。克服在老年AD患者中诱导安全、经济和足够的免疫反应相关的问题，将需要开发合适的疫苗和策略，以避免与接种疫苗的老年AD患者相关的不良事件。这项建议的目标是设计一种适合于在AD患者中快速转化为临床试验的疫苗，使用APP/TG模型识别与主动和被动接种策略相关的危险因素，并测试神经血管保护方法作为免疫治疗的补充。因此，我们将这一竞争性更新应用分为三个重点领域(AIMS)，这三个领域将共同帮助克服Abeta免疫治疗面临的重大障碍：1)设计和表征DNA和重组蛋白表位疫苗的免疫应答，该疫苗由三个主要Abeta B细胞表位(Abeta1-11)、一个外来的混杂Th2表位(PADRE)和一个强大的Th2分子佐剂巨噬细胞衍生趋化因子(MDC)组成；2)观察老年(16-20个月)和高龄(20-24个月)APP/Tg2576和TG-Swdi小鼠主动和被动Abeta免疫治疗后对Abeta的清除和神经血管病变易感性的差异；3)研究神经血管保护策略是否能减轻抗Abeta抗体诱导的APP/Tg2576和TG-Swdi小鼠的微出血。这项提议的目标是开发一种安全有效的治疗阿尔茨海默病的疫苗。该疫苗旨在利用患者自身的免疫系统清除大脑中与疾病有关的一种因子(β-淀粉样蛋白)。其他研究将侧重于确定与为老年患者接种疫苗有关的风险因素，并开发保护性疗法以消除这些风险因素。

DESCRIPTION (provided by applicant): Abeta-immunotherapy has received considerable attention as a promising approach for reducing the level of the Abeta in the CNS of AD patients. However, the first clinical trial, AN 1792, was halted when a subset of those immunized with Abeta42 developed adverse events in the central nervous system, and data from the trial indicate that there was a low percentage of responders and generally low liters in the patients that received the vaccine. Overcoming the problems associated with inducing a safe, economical, and adequate immune response in elderly AD patients will require the development of suitable vaccine and strategies to avoid adverse events associated with immunized elderly AD patients. The goals for this proposal are to design a vaccine that is suitable for rapid translation to a clinical trial in AD patients, to identify risk factors associated with active and passive vaccination strategies using APP/Tg models, and to test neurovascular protective approaches as an addendum to immunotherapy. Accordingly, we have divided this competitive renewal application into three areas of focus (Aims) that collectively will help overcome the significant hurdles facing Abeta-immunotherapy: 1) To design and characterize the immune response to DNA and recombinant protein epitope vaccines composed of three copies of the major Abeta B cell epitope (Abeta1-11), a foreign promiscuous Th2 epitope (PADRE), and a robust Th2 molecular adjuvant, macrophage derived chemokine (MDC); 2) To investigate the differences in clearance of Abeta and susceptibility to neurovascular pathology in old (16-20 months) and very old (20-24 months) APP/Tg2576 and Tg-SwDI mice after active or passive Abeta-immunotherapy; 3) To investigate whether neurovascular protective strategies can attenuate the anti-Abeta antibody-induced microhemorrhages in APP/Tg 2576 and Tg- SwDI mice. The goals of this proposal are to develop a safe and effective vaccine for treating Alzheimer's disease. The vaccine is designed to use the patient's own immune system to clear the brain of a factor (beta-amyloid) that has been linked to the disease. Additional studies will focus on identifying risk factors associated with immunizing elderly patients and developing protective therapies to eliminate these risk factors.