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，她提出了一种新的多学科方法来理解致敏肾移植受者的体液免疫反应。该奖项将为Yabu博士提供资源、指导和培训，以实现以下职业发展目标：(1)成为一名独立的肾移植转化临床研究人员；(2)成为应用免疫学方法治疗致敏患者的专家；(3)利用生物统计学方法了解致敏的危险因素。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（肾脏疾病临床研究专家）和三位共同导师组成的指导团队：Mark Davis博士（免疫学和四聚体检测的知名专家），Stephen Quake博士（微流体和深度测序的先驱）和Paul J. Utz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，仍然是成功肾移植的主要障碍。致敏患者占肾移植等待名单的25%，但每年只有6.5%的致敏患者被移植。尽管实施了脱敏策略，但许多患者由于不明原因未能反应，排异和移植物损失的比率很高。目前脱敏治疗的进展受到以下因素的阻碍

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.