Immune injury as a driver for the development of ascending aortic aneurysms and dissections

免疫损伤是升主动脉瘤和夹层发展的驱动因素

基本信息

批准号：
10454854
负责人：
Zhihua Jiang
金额：
$ 59.01万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/10454854
关键词：
Abdomen Ablation Acute Address Adoptive Cell Transfers Adoptive Transfer Affect Animal Model Aorta Aortic Aneurysm Aortic Rupture Autoantigens B-Lymphocytes Back Biological Blood C3AR1 gene CD19 gene CD4 Positive T Lymphocytes Cells Chronic Clinical Complement Complement 3a Complement 5a Coupled Data Decision Making Deposition Development Disease Dissection Equilibrium Event Feedback Foundations Future Genes Genetic Growth Human IL5 gene Immune Immune System Diseases Immune response Immunity Immunology Immunotherapy Inflammatory Response Injury Interferon Type II Interferons Interleukin-12 Intervention Lead Life Light Measures Medial Mediator of activation protein Mission Modeling Modification Molecular Mus Natural History Pathway interactions Patients Pharmacology Phenotype Regulation Risk Factors Role Rupture Shapes Signal Transduction Smooth Muscle Myocytes Solid Specimen Surrogate Endpoint T-Lymphocyte Testing Th2 Cells Thoracic Aortic Aneurysm Tissues Transforming Growth Factor beta United States Work adaptive immunity arm ascending aorta base cell mediated immune response complement system cytokine druggable target eosinophil human subject immunoregulation insight mouse model neutrophil novel peripheral blood polarized cell prevent receptor restoration therapeutic development transcription factor translational potential

项目摘要

Abstract Acute aortic dissection, particularly the type A dissection (AAD), is a life-threatening condition. Currently, there are no effective measures to prevent its onset and progression. A major barrier to satisfy these critical, unmet clinical needs is the poor understanding of the mechanisms that drive AAD development. AADs usually occur in aortas suffering progressive aneurysmal degeneration. However, compelling clinical evidence suggests that AADs and aortic aneurysms precede through distinct biological pathways. Yet, uncoupling these pathways has been a challenging task due to the silent onset of aortic dissections in patients coupled with a lack of animal models capable of mimicking the development of AAD reliably. To address this issue, we created two novel mouse AAD models, termed as “aortic tear model” and “aortic rupture model”, respectively. The “aortic tear model” develops spontaneous aortic tears with few ruptures in mildly dilated ascending aortas, whereas the “aortic rupture model” features acute aortic dissections with a high rate (40%) of aortic rupture in the first week. Using these models, we tested the long-standing, but unproved, hypothesis—disorders of immune response promote AAD formation. We found that 1) development of aortic tears is paralleled with an increased CD4+ T- cells and CD19+ B-cells in the AAD tissue as well as in the peripheral blood; 2) Th2 polarization via adoptive transfer of ex vivo expanded Th2 cells or neutralization of the Th1 signature cytokine interferon gamma (INFγ) exaggerates AAD dilation; 3) complement components are upregulated and deposited in the medial layer of AADs; and 4) genetic shifting of T-cell-mediated immune response to a Th2 prominent immunity dramatically provokes aortic rupture (>90% in four weeks). These novel findings led to an overall hypothesis that skewing of the inflammatory response in the aneurysmal aortic wall to type 2 immunity promotes AAD development. In this project, we will use genetic, adoptive cell transfer, and pharmacological approaches to evaluate the role of T- cells, B-cells, and complement system in regulating AAD development, with profile of immune cell subsets and cytokine milieu characterized to understand the cellular and molecular events engaged in promoting AAD formation. Critical findings will be validated for their implication across different mouse models, and more importantly, their relevance to human AAD development. Completion of this project will lay a solid foundation for future studies to develop immunotherapies to prevent AAD formation.

抽象的急性主动脉夹层，特别是A型夹层（AAD），目前是一种危及生命的疾病。没有有效的措施来阻止其发生和发展，这是满足这些关键的、未满足的主要障碍。临床需求是对驱动 AAD 发生的机制了解甚少。然而，令人信服的临床证据表明，主动脉患有进行性动脉瘤变性。 AAD 和主动脉瘤通过不同的生物学途径发生，然而，解开这些途径已成为可能。由于患者主动脉夹层的无声发作加上缺乏动物，这是一项具有挑战性的任务为了解决这个问题，我们创建了两本小说。小鼠AAD模型，分别称为“主动脉撕裂模型”和“主动脉破裂模型”。 “模型”在轻度扩张的升主动脉中出现自发性主动脉撕裂，很少有破裂，而 “主动脉破裂模型”以急性主动脉夹层为特征，第一周主动脉破裂率很高（40%）。使用这些模型，我们测试了长期存在但未经证实的假设——免疫反应紊乱我们发现，1) 主动脉撕裂的发生与 CD4+ T- 的增加是平行的。 AAD 组织以及外周血中的细胞和 CD19+ B 细胞 2) 通过过继的 Th2 极化；体外转移扩增的 Th2 细胞或中和 Th1 特征细胞因子干扰素 γ (INFγ) 夸大 AAD 扩张；3) 补体成分上调并沉积在内侧层 AAD；4) T 细胞介导的免疫反应显着转变为 Th2 显着免疫引起主动脉破裂（四个星期内>90%）。这些新发现导致了一个总体假设：主动脉破裂。动脉瘤性主动脉壁对 2 型免疫的炎症反应促进了 AAD 的发展。项目中，我们将使用遗传、过继细胞转移和药理学方法来评估 T-的作用细胞、B 细胞和补体系统在调节 AAD 发展中的作用，以及免疫细胞亚群的概况和细胞因子环境旨在了解促进 AAD 的细胞和分子事件关键发现将在不同的小鼠模型等中得到验证。重要的是，它们与人类 AAD 发展的相关性将为该项目的完成奠定坚实的基础。未来研究开发免疫疗法来预防 AAD 形成。