Improving Kidney Transplant Outcomes Using Novel B-cell Immune Profiling

使用新型 B 细胞免疫分析改善肾移植结果

• 批准号: 8680137
• 负责人: Julie M Yabu
• 金额: $ 13.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680137
• 关键词: Allografting; Antibodies; Antibody Formation; Antigens; Award; B cell repertoire; B-Lymphocytes; Binding; Biological Assay; Biological Markers; Biometry; Biostatistical Methods; Cell Therapy; Cells; Cellular biology; Clinical; Clinical Trials; Clonal Expansion; Cross-Sectional Studies; Cytometry; Data; Databases; Development; Diagnostic tests; Educational Curriculum; End stage renal failure; Event; Exposure to; Genomics; Goals; Graft Rejection; HLA Antigens; Health; Immune; Immune response; Immunoglobulin Variable Region; Immunologic Monitoring; Immunology; Immunotherapy; Incidence; Injury; Kidney Diseases; Kidney Transplantation; Lead; Major Histocompatibility Complex; Mass Spectrum Analysis; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Microfluidics; Nature; Outcome; Patients; Peptides; Pharmaceutical Preparations; Population; Pregnancy; Prevention strategy; Prospective Studies; Public Health; Receptors, Antigen, B-Cell; Recording of previous events; Relative (related person); Research; Research Design; Research Personnel; Resources; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Specificity; Techniques; Technology; Testing; Therapeutic; Time; Training; Transfusion; Translational Research; Transplant Recipients; Transplantation; Universities; Waiting Lists; Work; allograft rejection; base; career development; cell mediated immune response; clinical risk; cohort; deep sequencing; desensitization; design; effective therapy; improved; innovation; interdisciplinary approach; novel; success; symposium

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.

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、多学科的方法来了解致敏肾移植受者的体液免疫反应。这一奖项将使Yabu博士获得资源、指导和培训，以实现以下职业发展目标：(1)成为肾移植领域的独立、转化型临床研究人员；(2)成为免疫学方法应用于致敏患者方面的专家；以及(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博士组建了一个导师团队，由她的赞助人和主要导师Glenn Chertow博士(肾脏疾病临床研究专家)和三位共同导师组成：Mark Davis博士(著名免疫学专家和四聚体分析开发商)、Stephen Quake博士(微流体和深度测序领域的先驱)和Paul J.Utz博士(B细胞生物学和翻译研究专家)。肾移植是治疗终末期肾病最有效的方法。致敏，即人类白细胞抗原(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没有反应，排斥反应和移植物丢失的发生率很高。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，缺乏除人类白细胞抗原抗体以外的生物标记物，这可能是移植肾损伤的晚期和不可靠的标记物。通过使用一组接受脱敏和移植的致敏患者的样本，亚布博士将使用创新技术来确定B细胞免疫模式的纵向变化，这些变化会导致人类白细胞抗原抗体的产生，并与排斥反应和移植物丢失相关。亚布博士将利用斯坦福肾移植等待名单上的数据，找出与致敏相关的关键风险因素。提出了三个具体目标：目的1：通过对B细胞受体进行深度测序，确定脱敏患者的B细胞免疫谱系；目的2：利用CyTOF(R)质谱仪和MHC-多肽四聚体技术，表征脱敏患者中识别HLA抗原的B细胞的抗原特异性和细胞内信号网络；以及目标3：通过交叉检查Stanford肾移植和USRDS数据库，确定与致敏相关的临床危险因素。为亚布博士的培训设计了一套详细的课程，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，该研究将在 在K23奖励期结束前申请R01。