Multiple Approaches to ABeta Vaccination in Animal Mode*

动物模式 Aβ 疫苗接种的多种方法*

• 批准号: 6650974
• 负责人: David Hastings Cribbs
• 金额: $ 1.81万
• 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/6650974
• 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（申请人提供）：转基因APP的开发 (APP/Tg) 阿尔茨海默病 (AD) 小鼠模型提供了有价值的 测试潜在机制假设的实验系统 AD 的发病和进展，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已经 证明用原纤维 Abeta1-42 免疫 APP/Tg 小鼠 (Abeta42) 肽阻止沉积并启动现有的去除 来自大脑的阿贝塔沉积物。此外，已确定抗 Abeta 抗体可以保护小鼠免受阿尔茨海默病样的记忆丧失。 然而，关于其作用的一些问题仍未得到解答。 对 Abeta 的细胞免疫反应、Abeta 清除机制、潜力 对于自身免疫反应，以及与预期变异性相关的问题 MHC 的高度多态性导致的免疫反应。 Abeta肽免疫的成本、安全性和有效性都非常好 必须仔细评估的关键因素，以便制定 成功的疫苗。理想的 Abeta 疫苗应针对免疫反应 对清除至关重要的 Abeta 免疫原性表位，而不是 “无功能”抗体可能会导致不良副作用。 因此，当前提案的目标是： (i) 广泛审查 初级（IgM）和次级（IgGl、IgG2a）体液和细胞（T-辅助细胞 1， T辅助细胞2和CTL）在不同小鼠中对Abeta42的免疫反应 单倍型，包括 APP/Tg F1 动物； (ii) 分析其大小 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 展示肽，或这些免疫原的组合）； (三) 至 研究衰老对最佳疫苗接种免疫反应的影响 APP/Tg 小鼠的治疗方案； (iv) 测试该免疫接种的功效 APP/Tg 小鼠的行为障碍并分析阿尔茨海默病样 这些动物的病理学。因此，无论是预防还是治疗 将测试疫苗接种情况。