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.

项目总结/摘要 动脉粥样硬化斑块中自身抗原的鉴定促进了对抗体介导的动脉粥样硬化的研究。 动脉粥样硬化性心血管疾病（ASCVD）的发病机制。IgG抗体诱导的一个靶点是 ASCVD患者的主要蛋白是载脂蛋白A-I（ApoA-I），是高密度脂蛋白（HDL）的主要蛋白。虽然反- ApoA-I抗体已在小鼠和人类受试者中鉴定，其作用尚未阐明。 对ApoA-I的详细抗体谱的持续评估将提高我们对免疫系统的理解。 与ASCVD相关的反应。本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 我们的目标是，我们将在小鼠和患者中表征抗ApoA-I抗体应答的分子组分。 血清样本，并将这些因素与细胞相互作用，功能结果和动脉粥样硬化相关联 进展假设抗ApoA-I抗体可以表现出促炎或抗炎作用， 效果，取决于特定的抗体特性（即，抗原接合，亚类，表位特异性， Fc受体相互作用），并且这些作用在ASCVD患者中加剧或抑制。的理由 这项拟议中的研究是，了解体液免疫反应的一个组成部分， ASCVD将导致对潜在机制的更好理解和改善患者结局。这 假设将通过两个具体目标进行测试：1）阐明分子组成和功能 靶向ApoA-I的抗体在动脉粥样硬化小鼠模型中的意义;和2）描述 抗体谱和ASCVD事件之间的关系。目标1将 采用Venditto博士实验室开发的新型免疫调节策略， 调节抗体应答以阐明抗体/表位功能和在动脉粥样硬化进展中的作用。 在第二个目标中，将评估来自动脉粥样硬化多种族研究（梅萨）中患者的血清， 抗体谱，并与患者的结果相关。该方法是创新的，由于利用在 体内免疫调节的方法，可以改变抗ApoA-I IgG谱，和我们的能力，实现表位- 小鼠特异性免疫抑制。本文的研究成果具有重要的意义 将提高我们对B细胞介导的ApoA-I免疫应答的理解，以阐明抗体的作用 ASCVD进展。详细表征抗原、表位特异性、抗体亚类和 受体参与将增强对ASCVD的理解，以指导治疗开发和未来的努力 改善患者的风险分层程序，以降低患者的ASCVD负担。