Cell-Mediated and Autoimmune Responses in Abdominal Aortic Aneurysm (AAA)

描述(申请人提供)：主动脉瘤可以发生在主动脉的任何位置，但大多数发现在远端腹段，因此腹主动脉瘤或AAA。AAA在男性中更为常见，但小型动脉瘤的破裂风险在女性中高出三倍。在美国，主动脉瘤破裂每年导致15,000人死亡，使AAA成为导致男性死亡的第14大原因。AAA的研究和治疗每年产生的经济影响超过10亿美元。重要的是，AAA是唯一一种没有药物治疗的心血管疾病。已知的AAA特征包括板层结构破坏，肿瘤坏死因子-1和干扰素-3水平升高，以及以CD4+T细胞为主的致密性炎症。CD4+细胞通过分泌细胞因子和巨噬细胞募集来协调炎症过程和基质损伤。CD4+细胞的两个主要亚型是T调节细胞(Treg)和T效应细胞(Tef)。肿瘤坏死因子细胞通过分泌肿瘤坏死因子-1和干扰素-3，驱动侵袭性的促炎反应，导致显著的基质破坏。虽然比例很小，但Treg细胞通过以下方式发挥巨大的平衡作用：1)抑制TJeff细胞的增殖，2)抑制TJeff细胞和巨噬细胞分泌肿瘤坏死因子-1和干扰素-3，以及3)消除可能诱导自身免疫性炎症过程的自身反应性T细胞。我们假设，CD4+T细胞的内在差异与动脉瘤形成的易感性或抵抗力有关。初步数据显示，AAA患者和匹配的对照组循环中的CD4+细胞存在差异，这一假设得到了支持。为了验证这一假设，我们将研究从AAA和匹配的对照组患者中分离的循环CD4+细胞，以确定(目标1)关键免疫调节细胞因子(肿瘤坏死因子-1、干扰素-3、IL-2)的蛋白质表达差异，(目的2)确定将来自AAA和对照组患者的人CD4+细胞移植到人源化AAA小鼠模型中的效果，(目标3)确定AAA和对照组患者循环中Treg细胞的比例和功能(抑制TJeff细胞增殖或抑制TJeff细胞TNF-1、IFN-3的分泌)，以及(目标4)确定在AAA小鼠模型中操纵Treg细胞数量的效果。这些目标将使用分子方法、明确的研究患者群体和一个特征良好的AAA模型来实现，我们可以通过移植人类CD4+细胞来使其人性化。在确定疾病的基本原因方面，AAA的研究陷入僵局。我们相信，这项拟议的工作将确定导致AAA易感性的细胞类型。将未来的AAA研究集中在单一细胞类型上，将极大地增加发现导致AAA的基因产物组合的机会。这项研究的结果可能会对患者的护理产生立竿见影的影响，因为循环中的CD4+细胞的评估可以在动脉瘤之前或疾病的最早阶段确定AAA易感个体。

DESCRIPTION (provided by applicant): Aortic aneurysms can occur in any location of the aorta, but most are found in the distal abdominal segment, hence, abdominal aortic aneurysm or AAA. AAA is more common in men, but rupture risk for small aneurysms is threefold higher in women. Ruptured aortic aneurysms account for 15,000 deaths/yr in the U.S. making AAA the 14th leading cause of death in men. The economic impact of studies and treatment of AAA exceeds a billion dollars per year. Importantly, AAA is the only cardiovascular disease for which there is no medical therapy. Known features of AAA include destruction of the lamellar architecture, increased levels of TNF-1 and IFN-3, and dense inflammation with a predominance of CD4+ T cells. CD4+ cells orchestrate the inflammatory process and matrix damage through secreted cytokines and macrophage recruitment. The two main subtypes of the CD4+ population are the T regulatory cell (Treg) and the T effector cell (Teff). The Teff cells drive an aggressive proinflammatory response that leads to significant matrix destruction, in part through their secretion of TNF-1 and IFN-3. Although small in proportion, the Treg cells exert an enormous counterbalance to Teff cells by 1) inhibiting Teff cell proliferation, 2) inhibiting secretion of TNF-1 and IFN-3 from Teff cells and macrophages, and 3) eliminating autoreactive T cells that may induce an autoimmune inflammatory process. We hypothesize that intrinsic difference in CD4+ T cells are responsible for susceptibility or resistance to aneurysm formation. The hypothesis is supported by preliminary data showing differences in circulating CD4+ cells from AAA patients and a matched control group. The hypothesis will be tested by studying circulating CD4+ cells isolated from AAA and matched control patients defining (Aim 1) differences in protein expression of key immunoregulatory cytokines (TNF-1, IFN-3, IL-2), (Aim 2) determining the effects of engrafting human CD4+ cells from AAA and control patients into a humanized murine model of AAA, (Aim 3) determining the proportion and function (inhibition of Teff cell proliferation or inhibition of Teff cell TNF-1, IFN-3 secretion) of circulating Treg cells from AAA and control patients, and (Aim 4) determining the effects of manipulating Treg cell number in a murine model of AAA. These aims will be accomplished using molecular approaches, a defined study patient population, and a well characterized model of AAA that we can humanize by engrafting human CD4+ cells. AAA research is at an impasse with regard to identifying the basic causes of the disease. We believe the proposed work will identify the cell type that confers AAA susceptibility. Focusing future AAA research on a single cell type will greatly enhance the chances of finding the combination of gene products that cause AAA. The results of this study could have an immediate impact on patient care as evaluation of circulating CD4+ cells could identify AAA susceptible individuals before aneurysm or at the earliest stage of the disease.