Combining AD epitope vaccine with innate immunity

描述(申请人提供)：阿尔茨海默病(AD)是老年人中最常见的痴呆症，以独特的神经病理损害为特征，包括用于确认AD诊断的老年斑和神经原纤维缠结。APP转基因(APP/TG)小鼠形成类似AD的Abeta斑块的发展提供了强大的实验模型，用来检验AD发生和发展的机制以及潜在的治疗方法的假说。用纤维状Abeta42免疫APP/TG小鼠可诱导抗Abeta抗体，阻断沉积并促进APP/TG小鼠大脑中现有AA沉积的清除。此外，AP免疫似乎可以保护小鼠免受老年APP/TG小鼠出现的行为缺陷的影响。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”，利用先天免疫系统来放大和靶向针对AP的免疫反应。为了开发一种安全有效的Abeta免疫疗法，我们采取了四个策略(4个目标)：1)为了减少产生可能导致不良免疫反应的无功能自身抗体的可能性，并产生潜在的治疗性抗体，我们建议制备具有Abeta42自身B非自身T细胞表位的嵌合免疫原；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，我们建议去除自身Abeta T细胞表位，并将混杂的外源T细胞表位插入嵌合免疫原中；3)为了进一步避免产生潜在危险的Th-1介导的促炎反应和分化T细胞对Th-2表型的反应，我们建议使用来自天然免疫系统组件的分子佐剂；4)为了在APP/TG小鼠中产生有效的抗淀粉样蛋白抗体，我们建议用蛋白质、DNA或这些疫苗的组合免疫新型3xTg-AD和TG-Swdi小鼠，这些疫苗由2个拷贝的Abeta42强自身B细胞表位(2Aa1-11)和强混杂的外源T细胞表位Padre组成。我们相信，这种方法将为免疫疗法作为治疗AD的一种潜在的临床方法的总体疗效提供更全面的评估。

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.