Multiple Approaches to Abeta Vaccination in Animal Models

动物模型中 Abeta 疫苗接种的多种方法

基本信息

批准号：
7278237
负责人：
David Hastings Cribbs
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7278237
关键词：
AN-1792 Abeta clearance Active Immunization Active Immunotherapy Addendum Adjuvant Adverse event Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Formation Antigens Apoptosis Area Astrocytes Attention Attenuated Autoantigens B-Lymphocyte Epitopes B-Lymphocytes Blood - brain barrier anatomy Blood Cells Blood Vessels Brain Case Study Cells Chimeric Proteins Chronic Clinical Trials Cobra Venoms Complement Complement Activation Complement Inactivators Complex Custom Cutaneous DNA DNA Recombinant Proteins Data Deposition Development Diet Disease Dose Elderly Epitopes Event Fc Receptor Funding Gene Chips Gene Expression Genes Goals Hemorrhage Human Immune response Immune system Immunization Immunologic Monitoring Immunotherapy Impaired cognition Incidence Individual Inflammation Inflammatory Inflammatory Response Information Systems Interleukin-16 Link Localized Mediating Memory Meningeal Meningoencephalitis Microglia Minocycline Modeling Molecular Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neuroglia Outcome Passive Immunization Passive Immunotherapy Pathology Pathway interactions Patients Pattern Peripheral Personal Satisfaction Phase Physicians Population Predisposition Principal Investigator Process Property Proteins Protocols documentation QS21 Quil A Recombinants Reporting Research Personnel Risk Risk Factors Rodent Role STAT1 gene Safety Site T-Lymphocyte T-Lymphocyte Epitopes Testing Tg2576 Translating Translations Treatment Protocols Tumor Necrosis Factor-alpha Tumor Necrosis Factors Vaccination Vaccines Vertebral column Week aged autoreactive T cell base central nervous system injury cerebrovascular cobra venom factor cytokine design human TNF protein in vivo interest macrophage macrophage-derived chemokine mouse model novel older patient programs prototype research study response vaccination strategy vaccine delivery

项目摘要

DESCRIPTION (provided by applicant): Abeta-immunotherapy has received considerable attention as a promising approach for reducing the level of the Abeta in the CNS of AD patients. However, the first clinical trial, AN 1792, was halted when a subset of those immunized with Abeta42 developed adverse events in the central nervous system, and data from the trial indicate that there was a low percentage of responders and generally low liters in the patients that received the vaccine. Overcoming the problems associated with inducing a safe, economical, and adequate immune response in elderly AD patients will require the development of suitable vaccine and strategies to avoid adverse events associated with immunized elderly AD patients. The goals for this proposal are to design a vaccine that is suitable for rapid translation to a clinical trial in AD patients, to identify risk factors associated with active and passive vaccination strategies using APP/Tg models, and to test neurovascular protective approaches as an addendum to immunotherapy. Accordingly, we have divided this competitive renewal application into three areas of focus (Aims) that collectively will help overcome the significant hurdles facing Abeta-immunotherapy: 1) To design and characterize the immune response to DNA and recombinant protein epitope vaccines composed of three copies of the major Abeta B cell epitope (Abeta1-11), a foreign promiscuous Th2 epitope (PADRE), and a robust Th2 molecular adjuvant, macrophage derived chemokine (MDC); 2) To investigate the differences in clearance of Abeta and susceptibility to neurovascular pathology in old (16-20 months) and very old (20-24 months) APP/Tg2576 and Tg-SwDI mice after active or passive Abeta-immunotherapy; 3) To investigate whether neurovascular protective strategies can attenuate the anti-Abeta antibody-induced microhemorrhages in APP/Tg 2576 and Tg- SwDI mice. The goals of this proposal are to develop a safe and effective vaccine for treating Alzheimer's disease. The vaccine is designed to use the patient's own immune system to clear the brain of a factor (beta-amyloid) that has been linked to the disease. Additional studies will focus on identifying risk factors associated with immunizing elderly patients and developing protective therapies to eliminate these risk factors.

描述（由申请人提供）：Abeta 免疫疗法作为降低 AD 患者中枢神经系统中 Abeta 水平的有前途的方法而受到了相当大的关注。然而，第一项临床试验 AN 1792 由于部分接受 Abeta42 免疫的患者出现中枢神经系统不良事件而被终止，该试验的数据表明，应答者比例较低，且患者升数普遍较低接受疫苗的人。克服与在老年 AD 患者中诱导安全、经济和充分的免疫反应相关的问题将需要开发合适的疫苗和策略，以避免与免疫的老年 AD 患者相关的不良事件。该提案的目标是设计一种适合在 AD 患者中快速转化为临床试验的疫苗，使用 APP/Tg 模型识别与主动和被动疫苗接种策略相关的风险因素，并作为附录测试神经血管保护方法到免疫治疗。因此，我们将这一竞争性更新申请分为三个重点领域（目标），这些领域共同将有助于克服 Abeta 免疫疗法面临的重大障碍：1）设计和表征对由三个拷贝组成的 DNA 和重组蛋白表位疫苗的免疫反应主要 Abeta B 细胞表位 (Abeta1-11)、外来混杂 Th2 表位 (PADRE) 和源自巨噬细胞的强大 Th2 分子佐剂趋化因子（MDC）； 2) 研究老年（16-20个月）和非常老（20-24个月）APP/Tg2576和Tg-SwDI小鼠在主动或被动Abeta免疫治疗后Abeta清除率和对神经血管病理学易感性的差异； 3) 研究神经血管保护策略是否可以减轻 APP/Tg 2576 和 Tg-SwDI 小鼠中抗 Abeta 抗体诱导的微出血。该提案的目标是开发一种安全有效的疫苗来治疗阿尔茨海默病。该疫苗旨在利用患者自身的免疫系统清除大脑中与该疾病相关的因子（β-淀粉样蛋白）。其他研究将侧重于确定与老年患者免疫相关的风险因素，并开发保护性疗法来消除这些风险因素。