Expression Profiling In Acute Cardiac Allograft Rejectio

心脏移植后第一年内，急性同种异体心脏移植的细胞排斥反应仍然是发病率和死亡率的重要来源。在移植后的第一年，近63%的患者至少经历一次心脏排斥反应，其中约三分之一的患者将发生多次排斥反应。急性心脏排斥反应的临床症状相对非特异性(乏力、呼吸困难、低热)。目前尚无非侵入性诊断急性心脏排斥反应的方法。已经研究了几种方法，包括心电图学、超声心动图、核成像和磷光谱，但均未成功。目前诊断急性细胞排斥反应的金标准仍然是右室心内膜心肌活检。我们建议将功能基因组学应用于心脏移植急性排斥反应的研究。我们假设，循环外周血单个核细胞(主要是T淋巴细胞)的大规模表达谱将识别可以作为急性心脏细胞排斥反应的可靠生物标志物的基因。在该项目的初始阶段，将在同种异体移植物免疫耐受(无排斥)和同种异体移植物免疫不耐受(排斥)期间从心脏移植受者身上采集外周血单核细胞，以确定每种状态是否有独特的基因表达模式。在该项目的后期阶段，我们希望将这些特征转化为可接受的急性心脏移植细胞排斥反应的床边试验。除了开发一种生物标记物方法来诊断心脏移植患者的排斥反应外，表达谱还有可能识别免疫调节途径，这些途径可以作为免疫抑制治疗(合理的药物开发)的新靶点。

Acute cardiac allograft cellular rejection remains a significant source of morbidity and mortality within the first year after heart transplantation. In the first year after transplantation, nearly 63% of patients experience at least one episode of cardiac rejection and approximately one third of these patients will have multiple episodes. The clinical symptoms of acute cardiac rejection are relatively nonspecific (fatigue, dyspnea, low grade fever). No noninvasive method exists for the diagnosis of acute cardiac rejection. Several methodologies have been studied including electrocardiography, echocardiography, nuclear imaging, and phosphorus spectroscopy without success. The current gold standard for the diagnosis of acute cellular rejection remains right ventricular endomyocardial biopsy. We propose applying functional genomics to the study of acute cardiac allograft cellular rejection. We hypothesize that large scale expression profiling of circulating peripheral blood mononuclear cells (predominantly T lymphocytes) will identify genes that can serve as reliable biomarkers of acute cardiac cellular rejection. In the initial bench phase of the project peripheral blood mononuclear cells would be harvested from heart transplant recipients during periods of immunolgical tolerance of the allograft (no rejection) and immunologic intolerance of the allograft (rejection) to determine whether unique gene expression patterns are associated with each state. In the latter phase of the project we hope to translate these profiles into an acceptable bedside test for acute cardiac allograft cellular rejection. In addition to developing a biomarker approach to the diagnosis of rejection in cardiac transplant patients, expression profiling has the potential to identify immunoregulatory pathways that can serve as new targets for immunosuppressive therapy (rational drug development).