Combining AD epitope vaccine with innate immunity

AD表位疫苗与先天免疫相结合

• 批准号: 7072731
• 负责人: David Hastings Cribbs
• 金额: $ 42.14万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-25 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7072731
• 关键词: Alzheimer' s disease; B lymphocyte; T lymphocyte; amyloid proteins; antibody formation; chimeric proteins; disease /disorder model; genetically modified animals; immunoconjugates; immunotherapy; laboratory mouse; leukocyte activation /transformation; mannans; neurofibrillary tangles; nonhuman therapy evaluation; synthetic vaccines; therapy design /development; tissue engineering; vector vaccine

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.

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症，其特征是明显的神经病理学病变，包括用于确认 AD 诊断的老年斑和神经原纤维缠结。开发出类似 AD 的 Abeta 斑块的 APP 转基因 (APP/Tg) 小鼠提供了强大的实验模型，可用于测试 AD 发病和进展机制的假设以及潜在的治疗方法。用纤维状 Abeta42 免疫 APP/Tg 小鼠会诱导抗 Abeta 抗体，该抗体可阻止 APP/Tg 小鼠大脑中现有 Aa 沉积物的沉积并促进其清除。 此外，Ap 免疫似乎可以保护小鼠免受衰老 APP/Tg 小鼠中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。 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反应的非功能性自身抗体的可能性并产生潜在的治疗性抗体，我们建议制备具有自身B但非自身Abeta42 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，并为抗体生产提供足够的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细胞表位设计到嵌合免疫原中； 3）为了进一步避免产生潜在危险的Th-1介导的促炎反应的可能性，并使T细胞反应极化为Th-2表型，我们建议使用源自先天免疫系统成分的分子佐剂； 4) 为了在 APP/Tg 小鼠中产生有效的抗 α-淀粉样蛋白抗体，我们建议用蛋白质、DNA 或由 2 份强效抗体组成的这些疫苗的组合来免疫新型 3xTg-AD 以及 Tg-SwDI 小鼠。 Abeta42 (2 Aa1-11) 的自身 B 细胞表位和强混杂的外来 T 细胞表位 PADRE。我们相信，这种方法将为免疫疗法作为治疗 AD 的潜在临床方法的整体疗效提供更全面的评估。