Mucosal Abeta Vaccination: Modulating the Immune Response

粘膜 Abeta 疫苗接种：调节免疫反应

• 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
• 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' 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(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，没有足够的治疗方法来预防或治疗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，并改善其认知能力。不幸的是，2002年，由于约6%的AD患者出现脑膜脑炎，使用全长人Abeta多肽进行主动免疫的第二阶段临床试验停止。T细胞对全长Abeta多肽的识别可能已经诱导了自身免疫反应。一项新的临床试验正在进行中，目的是通过每月静脉注射人源化Abeta单抗来测试被动免疫的安全性。然而，仍然迫切需要一种长效、安全和有效的Abeta活性疫苗，以便更容易为更多的患者提供。在RO1的前4.5年，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。在这次竞争更新中，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免疫治疗将变得更安全。在目标1中，我们将使用3种给药途径(鼻内、皮下和经皮)在WT小鼠中测试针对Abeta B细胞表位的新型短Abeta免疫原，同时避免Abeta特异性T细胞表位。体液和细胞免疫反应将被描述。在目标2中，将在年轻的(预防的)和老年的(治疗的)J20 APP TG小鼠中测试最佳的短期Abeta免疫原/路线，并与使用我们的新的联合佐剂CpG/LT(R192G)诱导AR40/42免疫小鼠脑内T细胞增殖的全长Abeta免疫进行比较。将检查免疫反应，以及生化和神经病理以及行为变化。将进行免疫记忆测试。其次，我们假设补体和补体受体对于清除Abeta和免疫复合体是重要的，并可能在这种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样病理和疫苗相关不良事件(包括微出血)中的作用。我们已经产生了缺乏C3的APP TG小鼠，并将产生缺乏Mac-1的APP TG小鼠。这些小鼠将在AD样病理以及对主动和被动Abeta免疫的反应方面与J20 APP小鼠进行比较。LAY摘要：Aβ免疫疗法有可能预防和治疗阿尔茨海默病，但必须使其更安全。我们正在努力开发一种更安全的活性Abeta疫苗，并探索涉及补体及其受体的机制。