Genomic and Cellular Markers and Chronic Renal Allograft Function

描述(由申请人提供)：非裔美国人的慢性肾移植存活率比高加索人差，这可能是由于药物不坚持、免疫抑制药代动力学的种族差异、基因组因素、免疫反应性增强以及免疫动力学反应的种族差异。这项建议描述了一项基于我们的初步研究结果的试点研究，该研究表明种族和性别对肾移植后在给药间隔内免疫抑制药物暴露的患者间药物转运(基因和蛋白质)和免疫动力学反应的变异性有影响。这一应用的假设是，接受慢性、剂量调整的免疫抑制剂的肾移植受者在一段时间内表现出依赖于时间的药物转运体动力学和免疫反应，这受种族和性别的影响。其具体目的是：1)检查种族和性别对依赖时间的细胞外/细胞内免疫动力学反应的影响及其与细胞外/细胞内免疫抑制浓度的关系；2)调查患者之间和患者内部P-糖蛋白表达(基因和蛋白质)和功能与种族、性别和药物浓度之间的时间依赖模式。这些目标将扩大我们最初四个小时的MDR1基因表达、细胞内细胞因子(IL-2和IL-4)以及CD4+和CD8+T调节细胞、T Helper 1和T Helper 2淋巴细胞的细胞外免疫动力学反应的研究，以包括肾移植受者完整的12小时给药间隔。这项研究还将调查P-gp转运蛋白与免疫动力学反应的关系，包括种族、性别、年龄、药物暴露、肾功能、移植后时间、人类白细胞抗原相容和同时用药。这项研究的结果将提供初步数据，从目前用于创建结合细胞和基因组生物标记物的新方法的非特异性临床监测方法中创建一座桥梁。这种针对患者的方法将允许临床医生提供更个性化的免疫抑制治疗，并提高同种异体移植物的存活率。公共卫生相关性：该项目的意义在于，由于美国终末期肾脏疾病发病率的上升，对提高肾移植后移植肾存活率和功能的策略的需求日益增长。一个主要的担忧是观察到的种族差异，尽管药物治疗有所改善，但移植肾的结果并不理想。这项研究的结果将导致开发新的治疗指南以及潜在的生物标记物，包括种族和性别差异，以应对免疫抑制，并促进药物治疗的个体化和改善同种异体移植物的存活率和功能。

DESCRIPTION (provided by applicant): Chronic renal allograft survival is poorer in African Americans than Caucasians which may be due to medication non-adherence, racial differences in immunosuppressive pharmacokinetics, genomic factors, increased immunoreactivity, and racial variation in immunodynamic responses. This proposal describes a pilot study that is based on our preliminary findings that indicate race and gender impact on the interpatient variability in drug transport (gene and protein) and immunodynamic responses with immunosuppressive drug exposure within a dosing interval after renal transplantation. The hypothesis of this application is that individual renal allograft recipients receiving chronic, dose-adjusted immunosuppressives exhibit a time-dependent drug transporter dynamics and immunologic responses over a dosing interval that are influenced by race and gender. The specific aims are to: 1) Examine race and gender influence on time-dependent extracellular/intracellular immunodynamic responses and their relationship to extracellular/intracellular immunosuppressive concentrations; 2) Investigate interpatient and intrapatient, time-dependent patterns of P- glycoprotein expression (gene and protein) and function in relation to race, gender and drug concentrations. These aims will extend our initial four-hour studies of time-dependent responses of MDR1 gene expression, intracellular cytokines (IL-2 and IL-4) and extracellular immunodynamic responses of CD4+ and CD8+ T regulatory cells, T Helper 1 and T Helper 2 lymphocytes to include an entire twelve-hour dosing interval in renal transplant recipients. This study will also investigate the relationship of the P-gp transport protein and immunodynamic responses to race, gender, age, drug exposure, renal function, time post-transplant, HLA compatibility and concurrent medications. The results of this study will provide preliminary data to create a bridge from the non-specific clinical monitoring methods that are currently used to create a novel approach that incorporates cellular and genomic biomarkers. This patient specific approach will allow clinicians to provide more individualized immunosuppressive therapy and enhance allograft survival. PUBLIC HEALTH RELEVANCE: The significance of this project is related to the growing need for strategies that will increase allograft survival and function following renal transplantation due to the rising incidence of end stage renal disease in the United States. A primary concern is the observed racial disparity with regard to suboptimal renal allograft outcomes in spite of improved drug therapy. The results of this study will lead to the development of new therapeutic guidelines as well as potential biomarkers that incorporate race and gender differences in response to immunosuppression and facilitate individualization of drug treatment and improved allograft survival and function.