Improving Kidney Transplant Outcomes Using Novel B-cell Immune Profiling

描述（由申请人提供）：这是斯坦福大学移植肾病学家Julie Yabu博士的K23申请，他提出了一种新的多学科方法来了解致敏肾移植受者的体液免疫反应。该奖项将使Yabu博士获得资源，指导和培训，以实现以下职业发展目标：（1）成为肾移植的独立，转化临床研究人员;（2）成为免疫学方法应用于致敏患者的专家;（3）利用生物统计学方法了解致敏的风险因素。为了实现这些目标，Yabu博士组建了一个由她的赞助商和主要导师Glenn Chertow博士组成的指导团队（肾脏疾病临床研究专家）和三位共同导师：马克·戴维斯博士（著名的免疫学专家和四聚体测定的开发者），斯蒂芬·奎克博士（微流体和深度测序的先驱）和Paul J.乌茨博士（B细胞生物学和转化研究专家）。肾移植是治疗终末期肾病最有效的方法。致敏，人类白细胞抗原（HLA）抗体的形成，仍然是成功的肾移植的主要障碍。致敏患者占肾移植等候名单的25%，但每年只有6.5%的致敏患者接受移植。尽管实施了脱敏策略，但许多患者由于未知原因未能应答，排斥和移植物丢失率很高。目前脱敏治疗的进展受到以下因素的阻碍： 缺乏深入的免疫监测策略来指导治疗，缺乏HLA抗体以外的生物标志物，这可能是同种异体移植物损伤的晚期和不可靠的标志物。使用来自接受脱敏和移植的致敏患者队列的样本，Yabu博士将使用创新技术来确定导致HLA抗体产生的B细胞免疫谱的纵向变化，并与排斥反应和移植物丢失相关。利用来自斯坦福大学肾移植等待名单的数据，Yabu博士将确定与致敏相关的关键风险因素。提出了三个具体目的：目的1：通过对B细胞受体进行深度测序来确定经历脱敏的患者中B细胞的免疫库;目的2：使用CyTOF（R）质谱和MHC-肽四聚体技术来表征经历脱敏的患者中识别HLA抗原的B细胞的抗原特异性和细胞内信号传导网络;以及目的3：通过交叉检查斯坦福大学肾移植和USRDS数据库，确定与致敏相关的临床风险因素。为Yabu博士的培训设计了详细的课程，重点是应用免疫学，生物统计学和研究设计，科学会议和专业发展活动。这项计划中的研究将为在致敏肾移植受者中使用抗B细胞疗法的前瞻性研究奠定基础， 在K23奖励期结束前提交R 01申请。

DESCRIPTION (provided by applicant): This is a K23 application for Dr. Julie Yabu, a transplant nephrologist at Stanford University, who proposes a novel, multidisciplinary approach to understanding the humoral immune response in sensitized kidney transplant recipients. This award will allow Dr. Yabu the resources, mentoring, and training to achieve the following career development goals: (1) to become an independent, translational clinical researcher in kidney transplantation; (2) to become an expert in the application of immunological methods to sensitized patients; and (3) to utilize biostatistical methods to understand the risk factors for sensitization. To achieve these goals, Dr. Yabu has assembled a mentoring team comprised of her sponsor and primary mentor, Dr. Glenn Chertow (expert in the clinical investigation of kidney disease) and three co-mentors: Dr. Mark Davis (renowned expert in immunology and developer of tetramer assays), Dr. Stephen Quake (pioneer in microfluidics and deep sequencing), and Dr. Paul J. Utz (expert in B-cell biology and translational research). Kidney transplantation is the most effective treatment for end-stage kidney disease. Sensitization, the formation of human leukocyte antigen (HLA) antibodies, remains a major barrier to successful kidney transplantation. Sensitized patients comprise 25% of the kidney transplant waiting list, but only 6.5% of sensitized patients are transplanted each year. Despite the implementation of desensitization strategies, many patients fail to respond for unknown reasons and rates of rejection and graft loss are high. Current progress in desensitization therapies is hindered by the lack of in-depth immune monitoring strategies to guide therapy and the absence of biomarkers beyond HLA antibodies, which may be late and unreliable markers of allograft injury. Using samples from a cohort of sensitized patients undergoing desensitization and transplantation, Dr. Yabu will use innovative techniques to determine longitudinal changes in B-cell immune profiles leading to HLA antibody production and correlate with rejection episodes and graft loss. Using data from the Stanford kidney transplant waiting list, Dr. Yabu will identify key risk factors associated with sensitization. Three specific aims are proposed: Aim 1: To determine the immune repertoire of B-cells in patients undergoing desensitization by deep sequencing B-cell receptors; Aim 2: To characterize the antigen specificity and intracellular signaling networks of B-cells that recognize HLA antigens in patients undergoing desensitization using CyTOF(R) mass spectrometry and MHC- peptide tetramer technology; and Aim 3: To identify clinical risk factors associated with sensitization by cross- examining the Stanford kidney transplant and USRDS databases. A detailed curriculum focusing on applied immunology, biostatistics and study design, scientific conferences, and professional development activities have been designed for Dr. Yabu's training. The planned research will form the basis for prospective studies using anti-B-cell therapies in sensitized kidney transplant recipients to be proposed in an R01 application before the end of the K23 award period.