Mucosal ABeta Vaccination: Modulating the Immune Respon*

描述(由申请人提供)：阿尔茨海默病(AD)是一种 目前尚无有效预防措施的神经退行性疾病 或者治疗。淀粉样β蛋白(Abeta)的蓄积和伴随 炎症似乎在发病机制中起着关键作用。 神经元变性是阿尔茨海默病症状的基础。降低Abeta水平 和/或与其相关的炎症可延缓或防止 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，并可能导致 在改善行为方面。我们假设慢性粘膜Abeta免疫 用Abeta加粘膜佐剂诱导特异性和持续性的抗Abeta 通过Fc(γ)受体和/或补体清除的反应 受体，强烈地降低Aβ负荷，从而减少炎症和 神经元变性。这项提议的中心目标是推进这一点 为应用于人类做准备的假说。我们的具体目标是：1) 为了系统地确定有效的最佳免疫方案 粘膜(口腔或鼻腔)，经皮，或联合(例如，肠外，然后 野生型(非转基因)小鼠的鼻腔)Abeta疫苗，使用不同的 佐剂、Abeta多肽和给药程序；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 化学或遗传诱导的小鼠AA淀粉样蛋白减少 系统性AA淀粉样变性；3)研究Abeta免疫小鼠的作用机制 通过评估补体，补体受体(CR1和CR3)的作用 和Fc(Gamma)受体在免疫后Abeta还原中的作用 (使用我们从Aim 1优化的方案)免疫APP转基因小鼠 与Clq、C3或C3基因缺陷的小鼠杂交 Fc(伽马)受体RI和RIII。我们的计划利用了多条路线 免疫、多种佐剂和多种小鼠模型， 包括3个Aβ高表达转基因小鼠系(APP、PS 1、PSAPP)， 系统性AA淀粉样变性小鼠，以及3个基因敲除小鼠系(Clq-/-，C3-/- 和Fc(Gamma)R-/-)。多项结果衡量标准将决定 Abeta免疫对体液和细胞介导性反应以及 脑Aβ负荷及其相关炎症。我们相信我们的 经过验证的鼻黏膜免疫方法代表了一种独特的和 Abeta疫苗接种的有效途径可能是方便和 耐受性好，因此提供了一种非常有吸引力的预防和 治疗老年人阿尔茨海默病。

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.