Approaches to ABeta Vaccination in Animal Models

动物模型中 Aβ 疫苗接种的方法

• 批准号: 6429866
• 负责人: David Hastings Cribbs
• 金额: $ 37万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6429866
• 关键词: Alzheimer's disease; aging; amyloid proteins; genetically modified animals; laboratory mouse; lymphocyte; neuroimmunomodulation; nonhuman therapy evaluation; vaccine development; vaccines

DESCRIPTION (provided by applicant): The development of APP transgenic (APP/Tg) mouse models of Alzheimer's disease (AD) provides a valuable experimental system in which to test hypotheses on the mechanisms underlying the onset and progression of AD, as well as potential therapeutic approaches. Initial reports by Schenk et al., together with recent publications, have demonstrated that immunization of APP/Tg mice with fibrillar Abeta1-42 (Abeta42)peptide blocked the deposition and initiated the removal of existing Abeta deposits from the brain. In addition, it was established that anti-Abeta antibodies could protect mice from Alzheimer's disease-like memory loss. However, a number of questions remain unanswered regarding the role of cellular immune responses to Abeta, Abeta clearance mechanisms, the potential for an autoimmune response, and problems relating to the expected variability of immune responses resulting from the highly polymorphic nature of the MHC. The cost, safety and efficacy of immunization with Abeta peptide are all critical factors that must be carefully evaluated in order to develop a successful vaccine. The ideal Abeta vaccine should target the immune response to immunogenic epitopes of Abeta that are critical for clearance, and not "non-functional" antibodies that may contribute to unwanted side effects. Thus, the goals of the current proposal are: (i) to examine extensively the primary (IgM) and secondary (IgGl, IgG2a) humoral and cellular (T-helper 1, T-helper 2, and CTL) immune responses to Abeta42 in mice of different haplotypes, including APP/Tg F1 animals; (ii) to analyze the magnitude of humoral and cellular immune responses in high and low responders, as well as in APP/Tg mice, using multiple vaccine approaches (peptides, DNA, phage displaying peptide, or a combination of these immunogens); (iii) to investigate the affect of aging on the immune response to the best vaccination regimen in APP/Tg mice; (iv) to test the efficacy of this immunization on behavioral impairment of APP/Tg mice and analyze Alzheimer's disease-like pathology in these animals. Therefore, both prophylactic and therapeutic vaccination will be tested.

描述（由申请人提供）：App转基因的开发 （APP/TG）阿尔茨海默氏病的小鼠模型（AD）提供了有价值的 实验系统在其中测试假设的基础机制 AD的发作和进展以及潜在的治疗方法。 Schenk等人的初步报告，以及最近的出版物 证明用纤维纤维Abeta1-42对APP/TG小鼠进行免疫接种 （Abeta42）肽阻止了沉积并启动了现有的去除 Abeta沉积大脑。此外，已经确定了反对阿贝塔 抗体可以保护小鼠免受阿尔茨海默氏病的疾病样记忆丧失。 但是，关于 细胞免疫反应对Abeta，Abeta间隙机制，潜力 对于自身免疫响应以及与预期可变性有关的问题 由MHC高度多态性产生的免疫反应。 用Abeta肽免疫的成本，安全性和功效都是 必须仔细评估以开发一个关键因素 成功的疫苗。理想的Abeta疫苗应靶向免疫反应 对于Abeta的免疫原性表位，对于清除至关重要，而不是 可能导致不必要的副作用的“非功能”抗体。 因此，当前建议的目标是：（i）广泛检查 原发性（IgM）和次级（IgGL，IgG2a）的体液和细胞（t-Helper 1，1 T-Helper 2和CTL）对不同小鼠的Abeta42免疫反应 单倍型，包括App/TG F1动物； （ii）分析 高反应者和低反应者的体液和细胞免疫反应以及 在APP/TG小鼠中，使用多种疫苗方法（肽，DNA，噬菌体 显示肽，或这些免疫原子的组合）； （iii）至 研究衰老对最佳疫苗接种免疫反应的影响 APP/TG小鼠的方案； （iv）测试这种免疫的功效 APP/TG小鼠的行为障碍并分析类似阿尔茨海默氏病 这些动物的病理学。因此，预防性和治疗性 疫苗接种将进行测试。