Functional Consequences of Vaccination in AD Tg Mice

AD Tg 小鼠接种疫苗的功能后果

• 批准号: 7365155
• 负责人: David Morgan
• 金额: $ 27.53万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365155
• 关键词: Acceleration; Active Immunization; Address; Adoptive Transfer; Adrenal Cortex Hormones; Adverse event; Adverse reactions; Age; Alzheimer' 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; Condition; Coupled; Data; Data Reporting; Dementia; Deposition; Development; Dexamethasone; Diffuse; Dose; Elevation; 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; Numbers; Outcome; Participant; Passive Immunization; Passive Immunotherapy; Patients; Peptides; Peripheral; Phase II Clinical Trials; Predisposing Factor; Process; Property; Protocols documentation; Published Comment; Publishing; Rate; Reaction; Reporting; Risk; Role; Site; Specificity; Speed; T-Lymphocyte; Testing; Tg2576; Therapeutic Agents; Time; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Vaccination; Vaccines; age effect; anti-IgM; base; cognitive function; cohort; cost; humanized monoclonal antibodies; improved; member; mouse model; older patient; patient safety; success

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。