Mucosal Abeta Vaccination: Modulating the Immune Response

粘膜 Abeta 疫苗接种：调节免疫反应

• 批准号: 7569348
• 负责人: CYNTHIA A LEMERE
• 金额: $ 32.41万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 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/7569348
• 关键词: AN-1792; Abeta clearance; Active Immunization; Acute; Adjuvant; Adverse event; Age; Age-Months; Alzheimer' 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

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）是最常见的神经退行性疾病，然而，目前还没有足够的治疗方法来预防或治疗AD。自1999年以来，在阿尔茨海默病小鼠模型中，β免疫疗法已被证明可以降低大脑β水平并改善认知。不幸的是，2002年，由于约6%的阿尔茨海默病患者出现脑膜脑炎，一项使用全长人β肽进行主动免疫的II期临床试验被叫停。T细胞对全长β肽的识别可能引起了自身免疫反应。一项新的临床试验正在进行中，通过每月静脉注射人源化Abeta单克隆抗体来测试被动免疫的安全性。然而，迫切需要一种长效、安全和有效的阿贝塔活性疫苗，使更多的患者更容易获得这种疫苗。在这项研究的前4.5年，我们重点优化了野生型小鼠和AD小鼠模型的粘膜Abeta免疫。在这一竞争性更新中，我们的目标是产生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Aim 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）测试新的短β免疫原，该免疫原靶向β B细胞表位，同时避免β特异性T细胞表位。体液和细胞免疫反应将被描述。在Aim 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，并与使用我们的新型联合佐剂CpG/LT（R192G）诱导T细胞向AR40/42免疫小鼠脑内增殖的全长Abeta免疫进行比较。免疫反应，生化和神经病理，以及行为变化将被检查。免疫记忆将被测试。其次，我们假设补体和补体受体对于去除β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、ad样病理和疫苗相关不良事件（包括微出血）中的作用。我们已经生成了缺少C3的APP tg鼠标，并将生成缺少Mac-1的APP tg鼠标。这些小鼠将与J20 APP小鼠比较ad样病理和对主动和被动β免疫的反应。摘要：β免疫疗法具有预防和治疗阿尔茨海默病的潜力，但必须使其更安全。我们正在努力研制一种更安全的活性Abeta疫苗，并探索涉及补体及其受体的机制。