Functional Consequences of Vaccination in AD Tg Mice

AD Tg 小鼠接种疫苗的功能后果

基本信息

批准号：
7794996
负责人：
David Morgan
金额：
$ 27.26万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7794996
关键词：
Acceleration Active Immunization Address Adoptive Transfer Adrenal Cortex Hormones Adverse event Adverse reactions Age Alzheimer&apos s Disease Amyloid Amyloid deposition Antibodies Attention Automobile Driving Autopsy Award Behavioral Blood Vessels Brain C-terminal Carotid Artery Ulcerating Plaque Characteristics Clinical Trials Cognitive Cognitive deficits Coupled Data Data Reporting Dementia Deposition Development Dexamethasone Diffuse Dose Epitopes Excision Extravasation Gerda brand of difluprednate Grant Hemoglobin Hemorrhage Human IgG Receptors Immunoglobulin Fragments Immunoglobulin G Immunotherapeutic agent Immunotherapy Incidence Inflammation Injection of therapeutic agent Intraventricular Injections Lead Long-Term Effects Measures Mediating Memory Microglia Modeling Mus N-terminal Outcome Participant Passive Immunization Passive Immunotherapy Patients Peptides Peripheral Phase II Clinical Trials Predisposing Factor Process Property Protocols documentation Published Comment Publishing Reaction Reporting Risk Role Site Specificity Speed T-Lymphocyte Testing Tg2576 Therapeutic Agents Time Transgenic Animals Transgenic Mice Vaccination Vaccines adverse outcome age effect anti-IgM base cognitive function cohort cost humanized monoclonal antibodies improved member mouse model older patient patient safety success

项目摘要

Amyloid is a major pathological feature of Alzheimer's disease and a target of many therapeutic agents currently under development. In the first years of this grant we found that immunotherapyagainst the amyloidogenic ABpeptide, was remarkably effective in mouse models of amyloid deposition. Subsequent human clinical trials of active immunizationagainst the AJ3 peptide were suspended due to adverse events in a subset of patients. However, in at least one cohort of patients, individualsdeveloping antibodies which react with brain plaques benefited with cognitive stabilization. An alternative to vaccines, passive immunization has the advantages of controlled dosing and the ability to terminate immunotherapyif adverse reactions become manifest. Moreover, T-cell involvement, argued to be the basis for the adverse events in the suspended clinical trial, should not be present with adoptive transfer of antibody approaches. Preliminary data reported here with passive immunotherapy of old transgenic mice shows remarkable reversal of cognitive deficits and dramatic reductions in diffuse and fibrillar plaques. However, there were also increases in vascular amyloid deposits and a few sites containing extravascular hemoglobin. This competing continuation will seek passive immunization conditions which maximizethe cognitive benefits and reductions in parenchymal amyloid load while minimizingthe potentially deleterious vascular damage or other adverse consequences. This application will test passive immunotherapyin 3 aims. The first aim will evaluate the effects of age, amyloid load, and speed of amyloid removal on these processes. The second aim will compare antibodies with different epitopic specificities and measure the efficacy of different antibody fragments. In aim 3, alternative mechanisms will be investigated by examining mice with a preponderance of vascular deposits, the effects of corticosteroid suppression of microglia activation and the use of antibodies with strictly peripheral distribution . Success in these aims will identify conditions of passiveimmunization which maximizethe cognitive benefitswhile retaining high levels of patient safety for clinical trials in patients with Alzheimer's disease.

淀粉样蛋白是阿尔茨海默氏病的主要病理特征，也是许多治疗剂的靶标目前正在开发。在这笔赠款的头几年，我们发现免疫疗法淀粉样蛋白生成的肽在淀粉样蛋白沉积的小鼠模型中非常有效。随后的主动免疫的人类临床试验AJ3肽由于不良事件而被暂停患者子集。但是，在至少一群患者中，开发抗体的个体反应脑斑块受益于认知稳定。疫苗的替代品，被动免疫具有受控剂量的优势和终止免疫疗法的不良反应的能力变得明显。此外，T细胞的参与被认为是在暂停的临床试验不应通过抗体方法的产物转移。初步数据在此报道了旧转基因小鼠的被动免疫疗法显示出明显的认知逆转弥漫性和原纤维斑块的缺陷和急剧减少。但是，也有所增加血管淀粉样蛋白沉积物和一些含有血管外血红蛋白的部位。这个竞争的延续将寻求被动免疫条件，最大化认知益处和减少实质性淀粉样蛋白负荷，同时最大程度地减少潜在有害的血管损伤或其他不利结果。该应用将测试无源免疫疗法3的目标。第一个目标将评估年龄，淀粉样蛋白负荷和淀粉样蛋白去除速度对这些过程的影响。第二个目标将比较具有不同表现特异性的抗体并测量不同抗体片段的功效。在 AIM 3，将研究替代机制，通过检查小鼠的血管沉积，皮质类固醇激活的皮质类固醇的影响以及使用抗体严格的外围分布。这些目标的成功将确定被动免疫的条件最大化的认知益处，同时保留高水平的患者安全临床试验阿尔茨海默氏病的患者。