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 (INF?) 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.
Acute aortic dissection is a life-threatening aortic condition, with effective measures to prevent its onset or progression currently unavailable, due to poor understanding of the underlying mechanisms. Maturing from our preliminary studies, this project aims to evaluate the effect of disorder of T-cell immunity on the development of aortic dissections and elucidate the mechanisms that shape and reprogram the T-cell immunity in the aortic wall. Completion of this project may lead to identification of key cellular and molecular events that can serve as potential druggable targets for future development of therapeutics to prevent and treat aortic dissections.
