Mucosal ABeta Vaccination: Modulating the Immune Respon*

粘膜 Aβ 疫苗接种：调节免疫反应*

• 批准号: 6532582
• 负责人: CYNTHIA A LEMERE
• 金额: $ 42万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532582
• 关键词: Alzheimer's disease; amyloid proteins; antibody receptor; complement; complement receptor; enzyme linked immunosorbent assay; genetically modified animals; human tissue; laboratory mouse; mucosal immunity; neuroimmunomodulation; nonhuman therapy evaluation; vaccine development; vaccines

DESCRIPTION (provided by the applicant): Alzheimer's disease (AD) is a major neurodegenerative disease for which there is currently no effective prevention or treatment. Amyloid-beta protein (Abeta) accumulation and accompanying inflammation appear to play key roles in initiating the pathogenesis of the neuronal degeneration that underlies the symptoms of AD. Reducing Abeta levels and/or its associated inflammation may delay or prevent the onset of the disease. Recent reports by several research groups, including ours, have shown that Abeta vaccination lowers cerebral Abeta in transgenic mice and can result in improved behavior. We hypothesize that chronic mucosal Abeta immunization with Abeta plus mucosal adjuvants induces a specific and sustained anti-Abeta response that, via clearance through Fc(gamma)-receptors and/or complement receptors, strongly lowers Abeta burden, resulting in reduced inflammation and neuronal degeneration. The central goal of this proposal is to advance this hypothesis in preparation for application to humans. Our Specific Aims are: 1) to systematically determine the optimal immunization protocol for an effective mucosal (oral or nasal), transcutaneous, or combined (e.g., parenteral, then nasal) Abeta vaccine in wildtype (non-transgenic) mice, using various adjuvants, Abeta peptides and dosing schedules; 2) to determine the effectiveness of our optimized Abeta immunization protocol (from Aim 1) in each of 3 transgenic mouse models (APP, PS 1 and PSAPP) as well as for reduction of AA amyloid in a chemically- or genetically-induced mouse model of systemic AA amyloidosis; 3) to study the mechanism of Abeta immunization in vivo by assessing the role of complement, complement receptors (CR1 and CR3) and Fc(gamma)-receptors in Abeta reduction following immunization by immunizing (with our optimized protocol from Aim 1) APP transgenic mice crossbred with mice genetically deficient for either Clq, C3 or the Fc(gamma)-receptors RI and RIII. Our plan utilizes multiple routes of immunization, a diverse range of adjuvants and multiple mouse models, including 3 lines of Abeta-overproducing transgenic mice (APP, PS 1, PSAPP), mice with systemic AA amyloidosis, and 3 knockout mice lines (Clq-/-, C3-/- and Fc(gamma)R-/-). Multiple outcome measures will determine the effects of Abeta immunization on humoral and cell-mediated responses, as well as on cerebral Abeta burden and its associated inflammation. We believe our validated nasal mucosal immunization approach represents a unique and efficacious route for Abeta vaccination that could be convenient and well-tolerated, and thus provide a highly attractive method for prevention and treatment of AD in aged humans.

描述（由申请人提供）：阿尔茨海默病（AD）是一种主要的 神经退行性疾病，目前还没有有效的预防措施 或治疗。淀粉样β蛋白（Abeta）的积累和伴随 炎症似乎在启动糖尿病的发病机制中起关键作用， 神经元变性是AD症状的基础。降低Abeta水平 和/或其相关的炎症可以延迟或防止 疾病包括我们在内的几个研究小组最近的报告显示， Abeta疫苗接种降低了转基因小鼠的大脑Abeta， 行为的改善。我们假设慢性粘膜Abeta免疫 与Abeta加粘膜佐剂诱导特异性和持续的抗Abeta 通过Fc（γ）受体和/或补体清除的应答 受体，强烈降低Abeta负担，导致炎症减少， 神经元变性该提案的核心目标是推动这一点 为应用于人类做准备。我们的具体目标是：1） 系统地确定最佳免疫方案， 粘膜（口腔或鼻）、经皮或组合（例如，肠胃外，然后 鼻）Abeta疫苗在野生型（非转基因）小鼠中，使用各种 佐剂、Abeta肽和给药方案; 2）确定 我们优化的Abeta免疫方案（来自目标1）在 3种转基因小鼠模型（APP、PS 1和PSAPP）以及 减少化学或遗传诱导的小鼠模型中的AA淀粉样蛋白 系统性AA淀粉样变性; 3）研究Abeta免疫在AA中的作用机制。 通过评估补体、补体受体（CR 1和CR 3） 和Fc（γ）-受体在免疫后的Abeta减少中的作用 免疫（用我们从Aim 1优化的方案）APP转基因小鼠 与C1 q、C3或C2 q基因缺陷的小鼠杂交， Fc（γ）-受体RI和RIII。我们的计划利用多种途径， 免疫、多种佐剂和多种小鼠模型， 包括3个品系的A β过量产生转基因小鼠（APP、PS 1、PSAPP）， 具有系统性AA淀粉样变性的小鼠和3个敲除小鼠系（C1 q-/-，C3-/-， 和Fc（γ）R-/-）。多个结果指标将决定 Abeta免疫对体液和细胞介导的应答，以及 脑Abeta负荷及其相关炎症。我们相信我们的 经验证的鼻粘膜免疫方法代表了一种独特的， 用于Abeta疫苗接种的有效途径可能是方便的， 耐受性良好，因此提供了一种非常有吸引力的预防和治疗方法 治疗老年人的AD。