Mucosal Abeta Vaccination: Modulating the Immune Response

粘膜 Abeta 疫苗接种：调节免疫反应

基本信息

批准号：
7847751
负责人：
CYNTHIA A LEMERE
金额：
$ 4.67万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2011-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847751
关键词：
AN-1792 Abeta clearance Active Immunization Acute Adjuvant Adverse event Age Age-Months Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Antibodies Antigen-Antibody Complex Antigens Astrocytosis Autoimmune Process Autoimmune Responses B-Cell Activation B-Lymphocyte Epitopes B-Lymphocytes Behavioral Binding Biochemical Brain C3bi Carotid Artery Ulcerating Plaque Cell Separation Cell surface Cerebrum Clinical Trials Cognition Cognitive Complement Complement 3a Complement 5a Complement Activation Complement Inactivators Complement Receptor Complement component C4a Custom Data Deposition Development Endothelial Cells Enrollment Enzyme-Linked Immunosorbent Assay Escherichia coli heat-labile toxin Euthanasia Evaluation Event Excision Funding Future Goals Human ITGAM gene Immune response Immunization Immunohistochemistry Immunologic Memory Immunoprecipitation Immunotherapy Impaired cognition In Vitro Infiltration Inflammation Mediators Inflammatory Inflammatory Response Intranasal Administration Kidney LT(R192G)Length Liver Macrophage-1 Antigen Meningoencephalitis Microglia Modeling Monitor Monoclonal Antibodies Mus N-terminal Nerve Degeneration Neurodegenerative Disorders Outcome Measure Passive Immunization Passive Immunotherapy Pathology Patients Peptides Performance Phagocytes Phagocytosis Phase II Clinical Trials Plasma Play Prevention Proteins QS21 Reaction Reporting Research Personnel Role Route Safety Spleen Splenocyte T-Cell Proliferation T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic Therapy Clinical Trials Toxic effect Transgenic Mice Vaccination Vaccines Vascular Permeabilities Wild Type Mouse Work autoreactive T cell behavior test cytokine design dimer enterotoxin LT enzyme linked immunospot assay improved in vivo intravenous injection macrophage monomer morris water maze mouse model novel novel therapeutics particle patient population prevent programs receptor response safety testing subcutaneous tau phosphorylation vaccine safety

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of neurodegeneration however, adequate therapies do not exist to prevent or treat AD. Since 1999, Abeta immunotherapy has been shown to lower cerebral Abeta levels and improve cognition in AD mouse models. Unfortunately, a Phase II clinical trial of active immunization using full-length human Abeta peptide was halted in 2002 due to the onset of meningoencephalitis in ~6% of AD patients. T cell recognition of the full-length Abeta peptide may have induced an autoimmune response. A new clinical trial is underway to test the safety of passive immunization by monthly intravenous injections of humanized Abeta monoclonal antibodies. However, an urgent need remains for a long-lasting, safe and effective active Abeta vaccine that would be more readily available to a larger population of patients. In the first 4.5 years of this RO1, we focused on optimization of mucosal Abeta immunization in wild-type mice and AD mouse models. In this competitive renewal, our goals are to generate a safe and effective active Abeta vaccine and, to define the roles of complement and complement receptors in Abeta clearance and vaccine-related adverse events. First, we hypothesize that Abeta immunotherapy will be made safer by avoiding an Abeta-specific cellular immune response. In Aim 1, we will test novel short Abeta immunogens that target Abeta B cell epitopes while avoiding Abeta-specific T cell epitopes using 3 routes of administration (intranasal, subcutaneous, and transcutaneous) in WT mice. Humoral and cellular immune responses will be characterized. In Aim 2, the best short Abeta immunogens/routes will be tested in young (prevention) and old (therapeutic) J20 APP tg mice and compared with full-length Abeta immunization using our new combined adjuvants CpG/LT(R192G) that induced T cell proliferation into brains of AR40/42 immunized mice. Immune responses, as well as biochemical and neuropathological, and behavioral changes will be examined. Immunologic memory will be tested. Second, we hypothesize that complement and complement receptors are important for removal of Abeta and immune complexes, and may play a role in the safety of such a vaccine. In Aim 3, we will determine the roles of complement C3 and complement receptor CR3 (Mac-1, CD11b/CD18) in Abeta clearance, AD-like pathology, and vaccine-related adverse events including microhemorrhage. We have generated APP tg mice lacking C3 and will generate APP tg mice lacking Mac-1. These mice will be compared to J20 APP mice for AD-like pathology and response to active and passive Abeta immunization. Lay Summary: Abeta immunotherapy has the potential to prevent and treat Alzheimer's disease but must be made safer. We are working towards a safer active Abeta vaccine and exploring mechanisms involving complement and its receptors.

描述（由申请人提供）：阿尔茨海默氏病（AD）是神经变性的最常见形式，但是，没有足够的疗法来预防或治疗AD。自1999年以来，ABETA免疫疗法已被证明可以降低脑ABETA水平并改善AD小鼠模型的认知。不幸的是，由于约6％的AD患者的脑膜脑炎发作，使用全长人ABETA肽进行主动免疫的II期临床试验在2002年停止了。全长ABETA肽的T细胞识别可能已诱导自身免疫反应。正在进行一项新的临床试验，以测试人源化ABETA单克隆抗体的每月静脉注射被动免疫的安全性。但是，迫切需要进行持久，安全有效的主动ABETA疫苗，这对于较大的患者更容易获得。在此RO1的前4。5年中，我们专注于野生型小鼠和AD小鼠模型中粘膜Abeta免疫的优化。在这种竞争性更新中，我们的目标是生成安全有效的主动ABETA疫苗，并定义补体和补体受体在Abeta清除率和与疫苗相关的不良事件中的作用。首先，我们假设通过避免ABETA特异性细胞免疫反应，将使Abeta免疫疗法更安全。在AIM 1中，我们将测试靶向Abeta B细胞表位的新型短ABETA免疫原子，同时避免使用WT小鼠中3种给药途径（内鼻内，皮下和经皮）避免ABETA特异性T细胞表位。体液和细胞免疫反应将被表征。在AIM 2中，最好的短ABETA免疫/路线将在年轻（预防）和旧（治疗）J20 APP TG小鼠中进行测试，并使用我们的全长ABETA免疫使用我们的新组合佐剂CPG/LT（R192G）进行测试，这些佐剂CPG/LT（R192G）将T细胞促进T细胞的AR40/42/42免疫小鼠的大脑促进。将检查免疫反应以及生化和神经病理学以及行为改变。免疫记忆将进行测试。其次，我们假设补体和补体受体对于去除Abeta和免疫复合物很重要，并且可能在这种疫苗的安全性中发挥作用。在AIM 3中，我们将确定补体C3和补体受体CR3（MAC-1，CD11b/CD18）在ABETA清除，类似AD样病理学和疫苗相关的不良事件中的作用。我们已经生成了缺乏C3的应用TG小鼠，并且会生成缺乏Mac-1的应用TG小鼠。这些小鼠将与J20 App小鼠进行AD样病理和对主动和被动ABETA免疫的反应进行比较。 LIE摘要：Abeta免疫疗法有可能预防和治疗阿尔茨海默氏病，但必须使其更安全。我们正在努力采用更安全的主动Abeta疫苗，并探索涉及补体及其受体的机制。