Impact of T Cell Co-signaling on Cardiovascular Function in Children with Chronic Kidney Disease

摘要 慢性肾脏疾病(CKD)会增加患心血管疾病(CVD)的风险。瞄准 传统的心血管疾病危险因素并未显著改善CKD人群的预后，突显出 需要更好地了解和识别适合慢性肾脏病治疗的早期危险因素 人口。在动物模型中的严格研究现在支持T细胞在心脏发病机制中的作用 压力过载和CKD引起的失效。此外，还有几项观察性研究表明 显示晚期白血病患者分离的T细胞有反复激活和功能改变的迹象 CKD。CKD儿童还会积聚T细胞，表面表达的重要共信号发生变化 途径，即CD57的获得和CD28的下调，这预示着对联合- 激活的信号检查点，并提示增加的促炎潜力。此外， 初步数据显示，舒张期功能与CD57或CD28的表达有关。 分离CKD患儿的T细胞。这一提议的首要假设是尿毒症 状态改变T细胞活性，有助于早期心血管重塑。中概述的实验 这项关于肾脏疾病试点和可行性临床研究资助(R21)的提案将测试 共刺激/共抑制通路的T细胞表达模式与 慢性肾脏病期间的亚临床心脏和血管功能障碍。这项研究结合了对 缺乏混杂的儿童CKD患者高维T细胞表型的亚临床脑血管病 合并症通常出现在成年人身上。共有40名患有晚期CKD的儿童(GFR和Lt；30毫升/分钟/1.73平方米)和 将招募20名年龄和性别匹配的健康对照组。CD57(CD57+)和CD28的T细胞表达 (CD28null)用流式细胞仪检测。临床获得的超声心动图将被评估为 舒张期功能和亚临床室功能障碍的新措施(全球纵向应变) 评价T细胞CD57和CD28表达与心肌功能障碍的关系。颈动脉 将对动脉内膜中层厚度(CIMT)、脉搏波速度(PWV)和血流介导的扩张(FMD)进行研究 在同样招募的CKD受试者中进行检查，以询问动脉增厚与 动脉硬化和内皮功能障碍分别与T细胞CD57和CD28表达有关。最后， 用于高维流式细胞仪数据(Spade、ViSNE和Citrus)的非监督聚类算法将 识别CD57+和CD28ullT上额外的共刺激和共抑制受体的表达模式 CKD患者的细胞提供对其功能能力的洞察并确定潜在的未来 免疫调节策略。将在CKD儿童中发现更多新的T细胞群 与健康对照组进行比较，并评估他们的频率与心血管疾病的相关性 措施。收集的数据将为扩大翻译和基础科学研究奠定前提。

Abstract Chronic kidney disease (CKD) confers increased risk for cardiovascular disease (CVD). Targeting traditional CVD risk factors has not significantly improved outcomes in the CKD population, underscoring the need for improved understanding and identification of early risk factors amenable to treatment in the CKD population. Rigorous studies in animal models now support a role for T cells in the pathogenesis of heart failure induced by pressure overload and CKD. In addition, there is are several observational studies that demonstrate signs of repeated activation and altered function of T cells isolated from patients with advanced CKD. Children with CKD also accumulate T cells with altered surface expression of important co-signaling pathways, namely the gain of CD57 and the downregulation of CD28, which predict decreased reliance on co- signaling checkpoints for activation and suggest increased pro-inflammatory potential. Furthermore, preliminary data demonstrates an association between diastolic function and expression of CD57 or CD28 on T cells isolated from children with CKD. The overarching hypothesis for this proposal is that the uremic state alters T cell activity contributing to early cardiovascular remodeling. The experiments outlined in this proposal for a Pilot and Feasibility Clinical Research Grant in Kidney Diseases (R21) will test the hypothesis that T cell expression patterns of co-stimulatory/co-inhibitory pathways are associated with subclinical cardiac and vascular dysfunction during CKD. The study combines in-depth assessment for subclinical CVD with high-dimensional T cell phenotyping in pediatric CKD patients who lack confounding comorbidities often present in adults. A total of 40 children with advanced CKD (GFR < 30 mL/min/1.73m2) and 20 age- and gender-matched healthy controls will be recruited. T cell expression of CD57 (CD57+) and CD28 (CD28null) will be measured by flow cytometry. Clinically-acquired echocardiograms will be evaluated for diastolic function and novel measures of subclinical ventricular dysfunction (global longitudinal strain) to evaluate for associations between T cell expression of CD57 and CD28 with myocardial dysfunction. Carotid intimal media thickness (cIMT), pulse wave velocity (PWV) and flow-mediated dilation (FMD) studies will be performed in the same recruited subjects with CKD to interrogate the relationships between arterial thickening, arterial stiffness, and endothelial dysfunction, respectively, and T cell expression of CD57 and CD28. Finally, unsupervised clustering algorithms for high-dimensional flow cytometry data (SPADE, viSNE, and Citrus) will identify expression patterns of additional co-stimulatory and co-inhibitory receptors on CD57+ and CD28null T cells in CKD patients to provide insight into their functional capacity and identify potential future immunomodulatory strategies. Additional novel T cell populations will be identified in children with CKD compared to healthy controls, and their frequencies evaluated for associations with the cardiovascular measures. Data collected will establish premise for expanded translational and basic science studies.