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病的主要病理特征，也是许多治疗药物的靶点目前正在开发中。在这笔资助的最初几年，我们发现针对淀粉样蛋白生成 AB 肽在淀粉样蛋白沉积的小鼠模型中非常有效。随后的由于 AJ3 肽主动免疫的人体临床试验中出现不良事件，该试验被暂停患者的子集。然而，至少在一组患者中，个体产生了反应性抗体大脑斑块有助于认知稳定。疫苗的替代方案，被动免疫具有剂量可控、不良反应可终止免疫治疗的优点变得明显。此外，T 细胞参与被认为是不良事件的基础暂停的临床试验，不应与过继转移抗体方法一起存在。初步数据据报道，对老年转基因小鼠进行被动免疫治疗显示出认知能力的显着逆转弥漫性斑块和纤维斑块的缺陷和显着减少。然而，也有增加血管淀粉样蛋白沉积物和少数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，最大限度地提高认知效益并减少实质淀粉样蛋白负荷，同时最大限度地减少潜在有害的血管损伤或其他不利影响结果。该应用程序将测试被动免疫疗法的 3 个目标。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位特异性的抗体并测量不同抗体片段的功效。在目标 3，将通过检查具有大量血管的小鼠来研究替代机制沉积物、皮质类固醇抑制小胶质细胞活化的作用以及使用抗体严格外围分布。这些目标的成功将确定被动免疫的条件最大限度地提高认知效益，同时保持临床试验的高水平患者安全阿尔茨海默病患者。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Short-term beta-amyloid vaccinations do not improve cognitive performance in cognitively impaired APP + PS1 mice.

短期 β-淀粉样蛋白疫苗接种不会改善认知受损的 APP PS1 小鼠的认知表现。

DOI：
发表时间：
2003-06
期刊：
影响因子：
1.9
作者：
Austin, L;Arendash, G W;Gordon, M N;Diamond, D M;DiCarlo, G;Dickey, C;Ugen, K;Morgan, D
通讯作者：
Morgan, D

Lifelong immunization with human beta-amyloid (1-42) protects Alzheimer's transgenic mice against cognitive impairment throughout aging.

人类 β-淀粉样蛋白 (1-42) 的终身免疫可保护阿尔茨海默病转基因小鼠在整个衰老过程中免受认知障碍。

DOI：
发表时间：
2005
期刊：
影响因子：
0
作者：
Jensen, M T;Mottin, M D;Cracchiolo, J R;Leighty, R E;Arendash, G W
通讯作者：
Arendash, G W

Improvement of a low pH antigen-antibody dissociation procedure for ELISA measurement of circulating anti-Abeta antibodies.

改进低 pH 抗原-抗体解离程序，用于 ELISA 测量循环抗 Abeta 抗体。

DOI：
发表时间：
2007-03-20
期刊：
影响因子：
2.4
作者：
Li, Qingyou;Gordon, Marcia;Cao, Chuanhai;Ugen, Kenneth E.;Morgan, Dave
通讯作者：
Morgan, Dave

Duration and specificity of humoral immune responses in mice vaccinated with the Alzheimer's disease-associated beta-amyloid 1-42 peptide.

接种阿尔茨海默病相关 β-淀粉样蛋白 1-42 肽疫苗的小鼠体液免疫反应的持续时间和特异性。

DOI：
发表时间：
2001-11
期刊：
影响因子：
0
作者：
Dickey, C A;Morgan, D G;Kudchodkar, S;Weiner, D B;Bai, Y;Cao, C;Gordon, M N;Ugen, K E
通讯作者：
Ugen, K E

Overcoming antigen masking of anti-amyloidbeta antibodies reveals breaking of B cell tolerance by virus-like particles in amyloidbeta immunized amyloid precursor protein transgenic mice.

克服抗淀粉样蛋白抗体的抗原掩蔽揭示了在淀粉样蛋白免疫的淀粉样蛋白前体蛋白转基因小鼠中，病毒样颗粒破坏了 B 细胞耐受性。

DOI：
发表时间：
2004-06-08
期刊：
影响因子：
0
作者：
Li, Qingyou;Cao, Chuanhai;Chackerian, Bryce;Schiller, John;Gordon, Marcia;Ugen, Kenneth E;Morgan, Dave
通讯作者：
Morgan, Dave