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

描述（由申请人提供）：主动脉瘤可发生在主动脉的任何位置，但大多数发生在远端腹段，因此称为腹主动脉瘤或AAA。AAA在男性中更常见，但女性中小动脉瘤的破裂风险高出三倍。在美国，主动脉瘤破裂每年造成15，000例死亡，使AAA成为男性死亡的第14大原因。研究和治疗AAA的经济影响每年超过10亿美元。重要的是，AAA是唯一没有药物治疗的心血管疾病。AAA的已知特征包括层状结构的破坏、TNF-1和IFN-3水平的增加以及以CD 4 + T细胞为主的致密炎症。CD 4+细胞通过分泌细胞因子和巨噬细胞募集协调炎症过程和基质损伤。CD 4+细胞的两种主要亚型是调节性T细胞（Treg）和效应性T细胞（Teff）。Teff细胞驱动积极的促炎反应，导致显著的基质破坏，部分通过其分泌TNF-1和IFN-3。尽管比例很小，但Treg细胞通过1）抑制Teff细胞增殖，2）抑制Teff细胞和巨噬细胞分泌TNF-1和IFN-3，和3）消除可能诱导自身免疫炎症过程的自身反应性T细胞，对Teff细胞发挥巨大的平衡作用。我们假设CD 4 + T细胞的内在差异是动脉瘤形成的易感性或抵抗性的原因。初步数据显示AAA患者和匹配对照组的循环CD 4+细胞存在差异，这一假设得到了支持。将通过研究从AAA和匹配的对照患者分离的循环CD 4+细胞来验证该假设，定义（目的1）关键免疫调节细胞因子的蛋白表达差异（TNF-1，IFN-3，IL-2），（目的2）确定将来自AAA和对照患者的人CD 4+细胞移植到AAA的人源化鼠模型中的效果，（目的3）确定来自AAA和对照患者的循环Treg细胞的比例和功能（Teff细胞增殖的抑制或Teff细胞TNF-1、IFN-3分泌的抑制），和（目的4）确定在AAA的鼠模型中操纵Treg细胞数量的效果。这些目标将使用分子方法、确定的研究患者人群和充分表征的AAA模型来实现，我们可以通过移植人CD 4+细胞来人源化AAA模型。AAA研究在确定疾病的基本原因方面陷入僵局。我们相信这项工作将确定赋予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大大提高发现导致AAA的基因产物组合的机会。这项研究的结果可能对患者护理产生直接影响，因为循环CD 4+细胞的评价可以在动脉瘤前或疾病的最早阶段识别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.