Detection and Clearance of AD Amyloid Lesions

AD 淀粉样蛋白病变的检测和清除

基本信息

批准号：
7474683
负责人：
THOMAS M WISNIEWSKI
金额：
$ 30.63万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7474683
关键词：
APP-PS1 Active Immunization Address Adjuvant Adverse effects Affinity Alzheimer&apos s disease model Amyloid Amyloid deposition Animal Model Animals Antibodies Antigens Attenuated Attenuated Vaccines Autopsy Behavioral Blood - brain barrier anatomy Blood Vessels Brain Cellular Immunity Cerebral Amyloid Angiopathy Cerebral hemisphere hemorrhage Cerebrum Clinical Clinical Trials Cognitive Data Deposition Detection Development Disease Effectiveness Elderly Encephalitis Funding Gadolinium Gastrointestinal tract structure Grant Hemorrhage Human Humoral Immunities Immune response Immunization Inflammatory Label Lead Lesion Life Ligands Link Lymphocytosis Measurement Methods Microscopy Modeling Monitor Monoclonal Antibodies Mus Numbers Oral Patients Peptides Peritoneal Personal Satisfaction Photons Plasma Population Control Prevention Prion Diseases Production Publishing Reporting Research Design Research Personnel Risk Role Route Salmonella Salmonella Vaccines Senile Plaques Source T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic Effect Tissues Toxic effect Transgenic Mice Vaccinated Vaccination Vaccines aluminum sulfate cerebrovascular concept cytokine design improved in vivo mouse model mucosal vaccination novel oral vaccine prevent response

项目摘要

DESCRIPTION (provided by applicant): In the initial funding period of this grant we first proposed the concept of a potentially safer vaccine approach for AD using A¿ homologous peptides which are non-toxic and non-fibrillogenic. In addition we pioneered the use of gadolinium labeled A¿3 ligands for in vivo detection of amyloid lesions in Tg AD mice. In this revised competing continuation we focus on our immunological approaches to bring them closer to potential clinical use. Extensive data from many groups has shown that in AD model animals vaccination against A(3 is an effective means of preventing amyloid deposition, in association with cognitive benefits. More limited data from the aborted human active vaccination trial suggests that this approach can lead to amyloid clearance and cognitive improvement. However encephalitis occurred in 6% of patients, which has been linked to excessive cell mediated immunity. In our further studies we plan to avoid this toxicity by using our non-toxic A¿ homologous peptides which have the T-cell epitopes removed or altered in conjunction with adjuvants that primarily stimulate a humoral immune response and are appropriate for human use. These include alum and Salmonella vaccine strains. A further potential toxicity linked with vaccination is hemorrhage associated with cerebral amyloid angiopathy (CAA), which we will address in our planned studies. This is an important issue as almost all AD patients at autopsy have CAA, with about 20% having severe CAA. The specific aims are: 1) Assess vaccination with two of our A¿ homologous immunogens using alum as an adjuvant in AD Tg models that either have predominantly parenchymal amyloid versus vascular amyloid deposition. Vaccination will be initiated at the start of deposition and also after deposition is established. 2) Assess mucosal vaccination using attenuated Salmonella expressing our A¿ homologous immunogens via an oral route. 3) Vaccinated animals will be characterized behaviorally. The amyloid burden will be determined as well as levels of soluble/insoluble/oligomeric A¿. In a subset of animals, whether clearance of existing amyloid deposits occurs will be determined in vivo using 2-photon microscopy. The Th-1 versus Th-2 response will be monitored by assessing cytokine production and specific antibody titers. Lay Summary: Active vaccination is an potential exciting therapy for AD; however, it can only be applied to patients if effective methods which are non-toxic can be developed. This application seeks to verify if this is possible.

描述（由申请人提供）：在本次拨款的初始资助期间，我们首先提出了使用 A¿ 的潜在更安全的 AD 疫苗方法的概念同源肽无毒且不会形成纤维，此外我们还率先使用钆标记的 A¿ 3 配体用于体内检测 Tg AD 小鼠中的淀粉样蛋白损伤。在这一修订后的竞争性延续中，我们重点关注我们的免疫学方法，以使它们更接近临床潜在用途。来自许多组的大量数据表明，在 AD 模型动物中接种 A( 3 是一种有效的淀粉样蛋白沉积方法，可防止与认知益处相关。来自已中止的人类主动疫苗接种试验的更有限数据表明，这种方法可以导致淀粉样蛋白清除和认知改善，但 6% 的人发生脑炎。在我们的进一步研究中，我们计划通过使用去除了 T 细胞表位的无毒 A¿ 肽或与主要刺激体液免疫的佐剂结合使用来避免这种毒性。这些包括明矾和沙门氏菌疫苗株，与疫苗接种相关的另一个潜在毒性是与脑淀粉样血管病（CAA）相关的出血，我们将在计划的研究中解决这一问题。这是一个重要问题，因为尸检时几乎所有 AD 患者都患有 CAA，其中约 20% 患有严重 CAA。具体目标是：1) 使用我们的两种 A¿ 评估疫苗接种情况。在主要具有实质淀粉样蛋白与血管淀粉样蛋白沉积的 AD Tg 模型中使用明矾作为佐剂的同源免疫原将在沉积开始时以及沉积建立后开始 2) 使用表达我们的 A 的减毒沙门氏菌评估粘膜疫苗接种。通过口服途径获得同源免疫原 3) 将测定接种疫苗的动物的行为特征以及可溶性/不溶性/寡聚 A 的水平。在一部分动物中，将使用 2 光子显微镜在体内确定是否发生现有淀粉样沉积物的清除。将通过评估细胞因子的产生和特异性抗体滴度来监测 Th-1 与 Th-2 反应。是一种潜在的令人兴奋的 AD 疗法；然而，只有能够开发出无毒的有效方法，它才能应用于患者。本申请旨在验证这是否可行。