Multiple Approaches to Abeta Vaccination in Animal Models

描述（由申请人提供）：Abeta免疫疗法作为降低AD患者中枢神经系统中Abeta水平的一种有前景的方法受到了相当大的关注。然而，第一项临床试验AN 1792在接种了Abeta42疫苗的患者中出现中枢神经系统不良事件时被叫停，试验数据表明，接种疫苗的患者中应答者比例低，总体升数低。克服在老年AD患者中诱导安全、经济和充分的免疫应答的相关问题，需要开发合适的疫苗和策略，以避免与免疫老年AD患者相关的不良事件。该建议的目标是设计一种适合快速转化为AD患者临床试验的疫苗，使用APP/Tg模型确定与主动和被动疫苗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，我们将这种竞争性更新应用分为三个重点领域（Aims），共同有助于克服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反应，重组蛋白表位疫苗由三个主要的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月龄）和极老年（20-24月龄）APP/Tg2576和Tg-SwDI小鼠在主动或被动Abeta免疫治疗后Abeta清除率和神经血管病变易感性的差异；3)探讨神经血管保护策略是否能减轻APP/Tg 2576和Tg- SwDI小鼠抗β抗体诱导的微出血。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该疾病有关的因子（β -淀粉样蛋白）。其他研究将侧重于确定与老年患者免疫相关的风险因素，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.