Mechanistic Role of CD4+ T-Cells in Atherosclerotic Renal Artery Stenosis

描述(由申请人提供)：动脉粥样硬化性肾动脉狭窄(ARAS)是指肾动脉狭窄导致流向肾脏的血流量减少，并导致肾萎缩和高血压的情况。ARAS是肾功能衰竭的主要原因。在65岁以上的人中有超过7%的人存在这种情况，在多达45%的冠状动脉疾病患者中存在这种情况，在同时患有II型糖尿病和高血压的患者中存在多达17%的情况。ARAS患者的最佳处理是有争议的，因为血运重建和/或药物治疗通常都不能改善肾功能。目前的研究范式表明炎性M1巨噬细胞是ARAS肾损伤发生发展过程中的免疫介质。然而，最近的研究表明，在狭窄的肾脏中，CD4+T细胞的激活和分化为炎性Th1T细胞可能是导致M1巨噬细胞募集和分化的最初事件。尽管T细胞和ARAS之间存在这种相关性，但T细胞被招募、激活和介导狭窄肾脏炎症、肾损伤和萎缩的发展的机制尚不清楚。这是拟议研究的重点。我们推测，肾树突状细胞通过促进M1巨噬细胞分化，非抗原依赖性地激活Th1T细胞并将其募集到狭窄的肾脏，从而介导损伤。为了检验这一假设，我们制定了三个具体目标。首先，我们将在小鼠模型中确定肾树突状细胞是否是肾动脉狭窄后CD4+T细胞募集所必需的。我们的假说预测，肾树突状细胞是CD4+T细胞募集到狭窄肾脏所必需的。为了验证这一观点，我们将在缺乏树突状细胞的小鼠模型上诱导肾动脉狭窄，并确定缺乏树突状细胞是否会降低CD4+T细胞的激活，从而保护狭窄的肾脏免受萎缩。其次，在小鼠模型中，我们将讨论抗原介导的T细胞激活是否对于参与肾动脉狭窄后的肾损伤的CD4+T细胞是必需的。我们将在一只只含有非自身抗原特异性T细胞的转基因小鼠中诱导肾动脉狭窄，并确定缺乏自身抗原是否能保护狭窄的肾脏免受萎缩。 第三，我们将确定Th1T细胞是否通过促进小鼠肾动脉狭窄后M1巨噬细胞的分化而参与肾损伤的发展。为了测试这一想法，我们将在T细胞无法分化为Th1细胞的小鼠和巨噬细胞无法分化为M1巨噬细胞的小鼠中诱导肾动脉狭窄。拟议的研究将确定可能针对有效治疗的免疫反应。因此，这些研究的结果将有助于更好地了解CD4+T细胞在ARAS的病理生理机制中的作用，并可能导致开发治疗该疾病的新疗法。

DESCRIPTION (provided by applicant): Atherosclerotic renal artery stenosis (ARAS) is a condition where narrowing of the renal artery decreases blood flow to the kidney and leads to development of renal atrophy and hypertension. ARAS is a major cause of renal failure. It is present in over 7% of individuals over 65 years, in up to 45% of patients with coronary artery disease, and in up to 17% of patients with both type II diabetes and hypertension. Optimal management of patients with ARAS is controversial as both revascularization and/or pharmaceutical treatment often fails to improve renal function. Current paradigms point to inflammatory M1 macrophages as the immune mediator in the development of renal injury in ARAS. However, recent studies suggest that CD4+ T cell activation and differentiation into inflammatory Th1 T cells might be the initial events that lead to M1 macrophage recruitment and differentiation in the stenotic kidney. Despite this correlation between T cells and ARAS, the mechanisms by which T cells are recruited, activated, and mediate development of inflammation, renal injury, and atrophy in the stenotic kidney are not well defined. This is the focus of the proposed studies. We hypothesize that the antigen-independent activation and recruitment of Th1 T cells into the stenotic kidney by renal dendritic cells mediates injury by promoting M1 macrophage differentiation. To test this hypothesis, we develop three specific aims. First, we will determine if renal dendritic cells are necessary for CD4+ T cell recruitment after renal artery stenosis in a mouse model. Our hypothesis predicts that renal dendritic cells are necessary for CD4+ T cell recruitment to the stenotic kidney. To test this idea, we will induce renal artery stenosis in a mouse model lacking dendritic cells and determine if lack of dendritic cells reduces CD4+ T cell activation and thereby protects the stenotic kidney from atrophy. Second, we will address whether antigen-mediated T cell activation is necessary for CD4+ T cell participation in kidney damage after renal artery stenosis in a mouse model. We will induce renal artery stenosis in a transgenic mouse containing only T cells that are specific for a non-self- antigen, and determine if lack of self-antigen protects the stenotic kidney from atrophy. Third, we will determine if Th1 T cells mediate the development of renal injury by promoting M1 macrophage differentiation after renal artery stenosis in mice models. To test this idea, we will induce renal artery stenosis in mice with T cells that are unable to differentiate into Th1 cells and in mice with macrophages that are unable to differentiate into M1 macrophages. The proposed studies will identify immune responses that could be targeted for effective treatment. Thus, the results of these studies will lead to a better understanding of the mechanistic role of CD4+ T cells in the pathophysiology of ARAS, and could potentially lead to development of novel therapy for treatment of this disease.