Understanding the role of anti-apolipoprotein A-I antibodies in atherosclerotic cardiovascular disease

了解抗载脂蛋白 A-I 抗体在动脉粥样硬化性心血管疾病中的作用

• 批准号: 10002615
• 负责人: Vincent Joseph Venditto
• 金额: $ 38.99万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002615
• 关键词: Anti-inflammatory; Antibodies; Antibody Response; Antibody Therapy; Antigen-Antibody Complex; Antigens; Antiinflammatory Effect; Apolipoprotein A-I; Arterial Fatty Streak; Atherosclerosis; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Blood Circulation; Cardiovascular Diseases; Cardiovascular system; Characteristics; Communities; Data; Development; Disease; Disease Outcome; Disease Progression; Epitopes; Evaluation; Event; Exhibits; Fc Receptor; Formulation; Foundations; Future; Goals; High Density Lipoproteins; Homeostasis; Human; IgG1; IgG3; Immune response; Immunization; Immunoglobulin G; Immunologics; Immunosuppression; Immunosuppressive Agents; Incidence; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-12; Investigation; Laboratories; Measures; Mediating; Molecular; Multi-Ethnic Study of Atherosclerosis; Multivariate Analysis; Mus; Obesity; Outcome; Outcomes Research; Participant; Pathogenesis; Patient-Focused Outcomes; Patients; Peptide antibodies; Phenotype; Plant Roots; Procedures; Property; Prospective cohort; Proteins; Protocols documentation; Research; Risk; Risk Factors; Risk stratification; Role; Sampling; Serum; Specificity; Stratification; TLR4 gene; Testing; Therapeutic antibodies; Time; adjudicate; base; burden of illness; cardiovascular disorder risk; cardiovascular health; cell mediated immune response; clinical risk; cohort; drug development; follow-up; functional outcomes; human subject; immunoregulation; improved; in vivo; inflammatory milieu; innovation; mouse model; new technology; new therapeutic target; novel; novel strategies; programs; prospective; protocol development; receptor; therapeutic development; treatment strategy; western diet

PROJECT SUMMARY/ABSTRACT The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediated pathogenesis of atherosclerotic cardiovascular disease (ASCVD). One target of IgG antibody induction in ASCVD patients is apolipoprotein A-I (ApoA-I), the major protein of high density lipoprotein (HDL). Although anti- ApoA-I antibodies have been identified in mice and human subjects, their role has not been elucidated. Continued evaluation of the detailed antibody profile of ApoA-I will improve our understanding of the immune responses associated with ASCVD. The overall goal of this project is to elucidate the role of anti-ApoA-I antibodies and to characterize their molecular composition and functional impact in ASCVD. To achieve this goal, we will characterize the molecular components of the anti-ApoA-I antibody response in mice and patient serum samples and correlate these factors with cellular interactions, functional outcomes and atherosclerosis progression. The hypothesis is that anti-ApoA-I antibodies can exhibit a pro-inflammatory or anti-inflammatory effect, depending on the specific antibody characteristics (i.e., antigen engagement, subclass, epitope specificity, Fc receptor interaction), and these effects are exacerbated or suppressed in ASCVD patients. The rationale for this proposed research is that understanding one component of the humoral immune response associated with ASCVD will lead to a better understanding of the underlying mechanisms and improved patient outcomes. This hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of antibodies targeting ApoA-I in mouse models of atherosclerosis; and 2) Delineate the association between antibody profiles and ASCVD events in a large community-based prospective patient cohort. Aim 1 will employ novel immunomodulation strategies, developed in Dr. Venditto's laboratory, to achieve epitope-specific modulation of antibody responses to elucidate antibody/epitope function and role in atherosclerosis progression. In the second aim, sera from patients in the Multi-Ethnic Study of Atherosclerosis (MESA) will be evaluated for antibody profiles and correlated with patient outcomes. The approach is innovative due to the utilization of in vivo immunomodulation approaches that can alter the anti-ApoA-I IgG profiles, and our ability to achieve epitope- specific immune suppression in mice. The proposed research is significant as the outcomes of this research will improve our understanding of B cell-mediated immune responses to ApoA-I to elucidate the role of antibodies on ASCVD progression. Detailed characterizations of the antigen, epitope specificity, antibody subclass and receptor engagement will enhance understanding of ASCVD to guide therapeutic development and future efforts to improve risk stratification procedures in patients to decrease the burden of ASCVD in patients.

项目摘要/摘要 动脉粥样硬化斑块中自身抗原的鉴定促使对抗体介导的研究 动脉粥样硬化心血管疾病（ASCVD）的发病机理。 IgG抗体诱导的一个靶标 ASCVD患者是载脂蛋白A-I（APOA-I），高密度脂蛋白（HDL）的主要蛋白质。虽然反 - 在小鼠和人类受试者中已经鉴定出ApoA-I抗体，其作用尚未阐明。 对ApoA-I的详细抗体概况的持续评估将提高我们对免疫的理解 与ASCVD相关的响应。该项目的总体目标是阐明抗Apoa-I的作用 抗体并表征其分子组成和在ASCVD中的功能影响。实现这一目标 目标，我们将表征小鼠和患者抗APOA-I抗体反应的分子成分 血清样品并将这些因素与细胞相互作用，功能结局和动脉粥样硬化相关联 进展。假设是抗Apoa-I抗体可以表现出促炎或抗炎 效果，取决于特定抗体特征（即抗原参与，亚类，表位特异性， FC受体相互作用），这些作用在ASCVD患者中加剧或抑制。理由 这项提出的研究是了解与相关的体液免疫反应的一个组成部分 ASCVD将更好地了解基本机制和改善患者结果。这 假设将通过两个特定目的进行检验：1）阐明分子成分和功能 靶向ApoA-I的抗体在动脉粥样硬化的小鼠模型中的含义； 2）描述协会 在大型基于社区的前瞻性患者队列中，抗体曲线和ASCVD事件之间。目标1意志 采用旺迪托博士实验室中开发的新型免疫调节策略，以实现特定的表位 抗体对阐明抗体/表位功能的调节和动脉粥样硬化进展中的作用。 在第二个目标中，将评估动脉粥样硬化多族裔研究（MESA）的血清 抗体谱并与患者结局相关。这种方法是创新的，因为 可以改变抗Apoa-i IgG谱的体内免疫调节方法，以及我们实现表位的能力 小鼠的特异性免疫抑制。拟议的研究很重要，因为这项研究的结果 将提高我们对B细胞介导的免疫反应的理解，以阐明抗体的作用 关于ASCVD的进展。抗原，表位特异性，抗体亚类的详细特征和 受体参与将增强对ASCVD的理解，以指导治疗发展和未来的努力 改善患者的风险分层程序以减轻患者的ASCVD负担。