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

摘要 急性主动脉夹层，尤其是A型夹层(AAD)是一种危及生命的疾病。目前，有 没有有效的措施来预防其发生和发展。满足这些关键的、未解决的问题的主要障碍 临床需求是对驱动AAD发展的机制的了解不足。AADS通常发生在 患有进行性动脉瘤样变性的大动脉。然而，令人信服的临床证据表明 AADS和主动脉瘤通过不同的生物学途径发生。然而，解除这些途径的耦合 由于患者无声地出现主动脉夹层，加上缺乏动物，这是一项具有挑战性的任务 能够可靠地模拟AAD发展的模型。为了解决这个问题，我们创作了两部小说 小鼠AAD模型，分别命名为“主动脉撕裂模型”和“主动脉破裂模型”。“主动脉撕裂” 模型“在轻度扩张的升主动脉中发生自发性主动脉破裂，但很少破裂，而 “主动脉破裂模型”的特点是急性主动脉夹层在第一周的主动脉破裂发生率很高(40%)。 使用这些模型，我们检验了长期存在但未经证实的免疫反应紊乱假说。 促进防御工事形成。我们发现：1)主动脉撕裂的发展与CD4+T细胞的升高是平行的。 AAD组织和外周血中的细胞和CD19+B细胞；2)过继Th2极化 体外扩增的Th2细胞的转移或Th1型细胞因子干扰素γ的中和 3)补体成分上调并沉积在大脑中动脉内侧层 AADS；以及4)T细胞介导的免疫反应显著地向Th2显著免疫转变 导致主动脉破裂(&gt；在四周内90%)。这些新的发现导致了一个总体假设，即偏向于 腹主动脉瘤壁对2型免疫的炎症反应促进了AAD的发展。在这 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- 细胞、B细胞和补体系统在调节AAD发展中的作用，免疫细胞亚群和 细胞因子环境以理解参与促进AAD的细胞和分子事件为特征 队形。关键的发现将在不同的小鼠模型中得到验证，以及更多 重要的是，它们与人类AAD发展的相关性。该项目的建成将为 未来的研究将开发免疫疗法来预防AAD的形成。

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.