Combining AD epitope vaccine with innate immunity

描述（由申请人提供）：阿尔茨海默病（AD）是老年人中最常见的痴呆形式，其特征在于独特的神经病理学病变，包括用于确认AD诊断的老年斑和神经系统缠结。APP转基因（APP/Tg）小鼠，开发AD样Abeta斑块的发展提供了强大的实验模型，其中测试的发病和AD的进展，以及潜在的治疗方法的机制的假设。用纤维状A β 42免疫APP/Tg小鼠诱导抗A β抗体，其阻断APP/Tg小鼠脑中现有Aa沉积物的沉积并促进其清除。 此外，用Ap免疫似乎保护小鼠免受在老化APP/Tg小鼠中发生的行为缺陷。 第一次临床试验的失败鼓励我们寻求替代免疫策略，使用Abeta作为免疫原和"分子佐剂"，其利用先天免疫系统来放大和靶向针对Ap的免疫应答。 我们采用了四重策略（4个目标）来开发安全有效的Abeta免疫疗法：1）为了降低产生可能导致不良免疫应答的非功能性自身抗体的概率并产生潜在的治疗性抗体，我们提出制备具有自身B但非自身T细胞表位的Abeta 42嵌合免疫原; 2）为了消除产生自身反应性T细胞的可能性并为抗体产生提供足够的T细胞帮助，我们提出去除自身Abeta T细胞表位并将混杂的外源T细胞表位工程化到嵌合免疫原中; 3）为了进一步避免产生潜在危险的Th-1介导的促炎性应答的可能性和抑制T细胞对Th-2表型的应答，我们建议使用源自先天免疫系统组分的分子佐剂; 4）为了在APP/Tg小鼠中产生有效的抗α-淀粉样蛋白抗体，我们提出用蛋白质、DNA或这些疫苗的组合免疫新的3xTg-AD以及Tg-SwDI小鼠，所述疫苗由2个拷贝的A β 42的强自身B细胞表位（2Aa1 - 11）和强混杂外源T细胞表位PADRE组成。我们相信，这种方法将提供一个更全面的评估免疫治疗的整体疗效作为一个潜在的临床方法治疗AD。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized by distinct neuropathological lesions, including senile plaques and neurofibrillary tangles that are used to confirm the diagnosis of AD. The development of APP transgenic (APP/Tg) mice that develop AD-like Abeta plaques provide powerful experimental models in which to test hypotheses on the mechanisms underlying the onset and the progression of AD, as well as potential therapeutic approaches. Immunization of APP/Tg mice with fibrillar Abeta42 induces anti- Abeta antibodies that block deposition and promoted clearance of existing Aa deposits in the APP/Tg mouse brain. In addition, immunization with Ap appears to protect mice from behavioral deficits that occur in aging APP/Tg mice. The failure of the first clinical trial has encouraged us to pursue alternative immunization strategies using Abeta as an immunogen and "molecular adjutants" that utilize the innate immune system to amplify and target the immune response against Ap. We have adopted a fourfold strategy (4 Aims) for developing a safe and effective Abeta immunotherapy: 1) To reduce the probability of generating non-functional auto-antibodies that may contribute to an adverse immune response and to generate potentially therapeutic antibodies, we propose to prepare chimeric immunogens that possess self-B, but non-self T cell epitope of Abeta42; 2) To eliminate the possibility of generation of auto-reactive T cells and to provide adequate T cell help for antibody production, we propose to remove the self- Abeta T cell epitope and engineer a promiscuous foreign T cell epitope into the chimeric immunogen; 3) To further avoid the possibility of generation of potentially dangerous Th-1 mediated proinflammatory responses and to polarize T cell response towards Th-2 phenotype, we propose to use molecular adjutants derived from the components of the innate immune system; 4) To generate potent anti-a-amyloid antibodies in APP/Tg mice, we propose to immunize novel 3xTg-AD, as well as Tg-SwDI mice with protein, DNA or a combination of these vaccines composed of 2 copies of the strong self-B cell epitope of Abeta42 (2 Aa1-11) and the strong promiscuous foreign T cell epitope, PADRE. We believe that this approach will provide a more comprehensive assessment of the overall efficacy of immunotherapy as a potential clinical approach for treating AD.