Understanding the role of immune complexes between apolipoprotein A-I and IgG in atherosclerotic cardiovascular disease

了解载脂蛋白 A-I 和 IgG 之间的免疫复合物在动脉粥样硬化性心血管疾病中的作用

• 批准号: 10634607
• 负责人: Vincent Joseph Venditto
• 金额: $ 37.6万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10634607
• 关键词: Acceleration; Anti-Inflammatory Agents; Antibodies; Antibody Response; Antigen-Antibody Complex; Antiinflammatory Effect; Apolipoprotein A-I; Arterial Fatty Streak; Atherosclerosis; Autoantibodies; Autoantigens; Autoimmune Diseases; Cardiovascular Diseases; Cell model; Cells; Characteristics; Circulation; Communities; Complex; Cultured Cells; Data; Death Rate; Development; Disease; Disease Progression; Epitopes; Evaluation; Event; Exhibits; Fc Receptor; Future; Goals; High Density Lipoproteins; Homeostasis; Human; IgG4; Immune System Diseases; Immune response; Immunization; Immunoglobulin G; Incidence; Inflammation; Inflammatory; Investigation; Laboratories; Measures; Mediating; Molecular; Multi-Ethnic Study of Atherosclerosis; Multivariate Analysis; Mus; Myocardial Infarction; Outcome; Outcomes Research; Participant; Pathogenesis; Patient-Focused Outcomes; Patients; Phenotype; Plasma; Procedures; Prospective cohort; Proteins; Protocols documentation; Receptor Signaling; Research; Risk; Risk Factors; Role; Sampling; Specificity; Stroke; Testing; adjudication; burden of illness; cardiovascular disorder risk; cardiovascular health; cardiovascular risk factor; clinical risk; cohort; drug development; follow-up; functional outcomes; human subject; immunoregulation; improved; in vitro activity; in vivo; innovation; male; mouse model; new therapeutic target; novel; novel strategies; novel therapeutics; obese patients; profiles in patients; programs; protocol development; receptor; response; risk stratification; therapeutic development; vaccination strategy; western diet

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. The PI has identified immune complexes formed between ApoA-I and IgG (ApoA-I/IgG IC) that exhibit anti-inflammatory characteristics and associate with decreased CVD risk. Continued evaluation of ApoA-I/IgG ICs will improve our understanding of this component of the immune responses associated with ASCVD. The overall goal of this project is to determine the role of ApoA-I/IgG ICs and elucidate their functional impact in ASCVD. To achieve this goal, we will characterize the molecular components of ApoA-I/IgG ICs in mouse and patient sera samples and correlate these factors with cellular interactions, functional outcomes and disease progression. The hypothesis is that ApoA-I/IgG ICs exhibit anti-inflammatory effects mediated through the inhibitory Fc-receptor depending on antibody characteristics (i.e. epitope specificity, subclass), and these effects are capable of suppressing inflammation and disease. 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 improve patient outcomes. Encouraged by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of ApoA-I/IgG ICs using cultured cells and mouse models of atherosclerosis; and 2) Determine the characteristics and anti-inflammatory activity of ApoA-I/IgG ICs from human plasma and delineate the association among ApoA- I/IgG ICs and ASCVD in a large community-based cohort. Aim 1 will employ novel immunomodulation strategies, developed in Dr. Venditto's laboratory, to achieve epitope-specific immune modulation of antibody responses in mice to elucidate antibody/epitope function and the role in atherosclerosis progression. Aim 2 will employ sera from human subjects to characterize antibody/epitope function and evaluate the association between ApoA-I/IgG ICs and disease progression in the Multi-Ethnic Study of Atherosclerosis (MESA). The approach is innovative due to the utilization of in vivo immunomodulation approaches to alter ApoA-I/IgG IC profiles, and our approach focused on obtaining detailed ApoA-I/IgG IC profiles in patients for association studies with disease. The proposed research is significant as the outcomes of this research will improve our understanding of antibody- mediated immune responses to ApoA-I to elucidate the role of antibodies on ASCVD progression. Detailed characterizations of the prefinalantigen, epitope specificity, antibody subclass and receptor engagement will enhance our understanding of ASCVD to guide therapeutic development and future efforts to improve risk stratification procedures to decrease the burden of ASCVD in patients.

动脉粥样硬化斑块中自身抗原的鉴定促使了抗体介导的研究

项目成果

University-pharmacy partnerships for COVID-19.

针对 COVID-19 的大学与药房合作伙伴关系。

• DOI: 10.1126/science.abe3339
• 发表时间: 2020
• 期刊: Science (New York, N.Y.)
• 作者: Venditto,VincentJ;Hudspeth,Brooke;Freeman,PatriciaR;Kebodeaux,Clark;Guy,RKiplin
• 通讯作者: Guy,RKiplin

Autoantibody Responses to Apolipoprotein A-I Are Not Diet- or Sex-Linked in C57BL/6 Mice.

• DOI: 10.4049/immunohorizons.2000027
• 发表时间: 2020-08-05
• 期刊: ImmunoHorizons
• 作者: Pitts MG;Nardo D;Isom CM;Venditto VJ
• 通讯作者: Venditto VJ

Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19.

• DOI: 10.3389/fimmu.2021.574425
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Venditto VJ;Haydar D;Abdel-Latif A;Gensel JC;Anstead MI;Pitts MG;Creameans J;Kopper TJ;Peng C;Feola DJ
• 通讯作者: Feola DJ

In vivo assessment of triazine lipid nanoparticles as transfection agents for plasmid DNA.

• DOI: 10.1039/d2bm01289h
• 发表时间: 2022-12-06
• 期刊: BIOMATERIALS SCIENCE
• 影响因子: 6.6
• 作者: Nardo, David;Pitts, Michelle G.;Kaur, Rupinder;Venditto, Vincent J.
• 通讯作者: Venditto, Vincent J.

Promoting Cultural Humility by Integrating Health Equity Literature into the Pharmacy Curriculum.

通过将健康平等文献纳入药学课程来促进文化谦卑。

• DOI: 10.3390/pharmacy10050116
• 发表时间: 2022-09-21
• 期刊: PHARMACY
• 影响因子: 2.2
• 作者: Venditto, Vincent J;Colon, Kristie
• 通讯作者: Colon, Kristie