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

• 批准号: 10204109
• 负责人: Zhihua Jiang
• 金额: $ 58.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 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/10204109
• 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; Structure; 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

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.

摘要