Combining AD epitope vaccine with innate immunity

AD表位疫苗与先天免疫相结合

• 批准号: 6880329
• 负责人: David Hastings Cribbs
• 金额: $ 41.84万
• 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/6880329
• 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（Alzheimer's disease， AD）是老年人最常见的痴呆形式，其特征是明显的神经病理病变，包括老年斑和神经原纤维缠结，可用于确认AD的诊断。APP转基因（APP/Tg）小鼠产生AD样β斑块的发展提供了强大的实验模型，用于测试AD发病和进展机制的假设，以及潜在的治疗方法。用纤原Abeta42免疫APP/Tg小鼠可诱导抗Abeta抗体，阻断沉积，促进APP/Tg小鼠脑内已有Aa沉积的清除。此外，Ap免疫似乎可以保护小鼠免受衰老APP/Tg小鼠的行为缺陷。第一次临床试验的失败促使我们寻求使用Abeta作为免疫原和“分子佐剂”的替代免疫策略，利用先天免疫系统来放大和靶向针对Ap的免疫反应。我们采用了四种策略（4个目标）来开发安全有效的Abeta免疫疗法：1)为了减少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Abeta42的自身b细胞而非自身T细胞表位的嵌合免疫原；2)为了消除自身反应性T细胞产生的可能性，并为抗体的产生提供足够的T细胞帮助，我们建议去除自身- β T细胞表位，并将混杂的外来T细胞表位植入嵌合免疫原中；3)为了进一步避免产生潜在危险的Th-1介导的促炎反应的可能性，并使T细胞对Th-2表型的反应极化，我们建议使用来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a-淀粉样蛋白抗体，我们提出用由2拷贝Abeta42强自身b细胞表位（2 a1-11）和强混杂外源T细胞表位PADRE组成的蛋白质、DNA或组合疫苗免疫新型3xTg-AD和Tg- swdi小鼠。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。