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：
7795028
负责人：
CYNTHIA A LEMERE
金额：
$ 32.09万
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：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7795028
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 response 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）：阿尔茨海默病（AD）是最常见的神经变性形式，然而，不存在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 AD 小鼠模型的大脑 Abeta 水平并改善认知能力。不幸的是，由于约 6% 的 AD 患者出现脑膜脑炎，使用全长人 Abeta 肽进行主动免疫的 II 期临床试验于 2002 年停止。 T 细胞对全长 Abeta 肽的识别可能诱导了自身免疫反应。一项新的临床试验正在进行中，以测试每月静脉注射人源化 Abeta 单克隆抗体被动免疫的安全性。然而，仍然迫切需要一种持久、安全和有效的活性 Abeta 疫苗，让更多患者更容易获得。在本 RO1 的前 4.5 年中，我们重点关注野生型小鼠和 AD 小鼠模型中粘膜 Abeta 免疫的优化。在这一竞争性更新中，我们的目标是生产一种安全有效的活性 Abeta 疫苗，并确定补体和补体受体在 Abeta 清除和疫苗相关不良事件中的作用。首先，我们假设通过避免 Abeta 特异性细胞免疫反应，Abeta 免疫疗法将变得更安全。在目标 1 中，我们将在 WT 小鼠中使用 3 种给药途径（鼻内、皮下和经皮）测试新型短 Abeta 免疫原，该免疫原靶向 Abeta B 细胞表位，同时避免 Abeta 特异性 T 细胞表位。将表征体液和细胞免疫反应。在目标 2 中，将在年轻（预防）和老年（治疗）J20 APP tg 小鼠中测试最佳的短 Abeta 免疫原/途径，并与使用我们新的组合佐剂 CpG/LT(R192G) 诱导 T 的全长 Abeta 免疫进行比较。 AR40/42 免疫小鼠大脑中的细胞增殖。将检查免疫反应以及生化和神经病理学以及行为变化。将测试免疫记忆。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，并且可能在此类疫苗的安全性中发挥作用。在目标 3 中，我们将确定补体 C3 和补体受体 CR3（Mac-1、CD11b/CD18）在 Abeta 清除、AD 样病理以及包括微出血在内的疫苗相关不良事件中的作用。我们已经生成了缺乏 C3 的 APP tg 小鼠，并将生成缺乏 Mac-1 的 APP tg 小鼠。将这些小鼠与 J20 APP 小鼠进行比较，以了解 AD 样病理学以及对主动和被动 Abeta 免疫的反应。总结：Abeta 免疫疗法具有预防和治疗阿尔茨海默病的潜力，但必须变得更安全。我们正在努力开发更安全的活性 Abeta 疫苗，并探索涉及补体及其受体的机制。