Understanding the Interface of Allo and Auto-Immunity: The Impact of Angiotensin II Type 1 Receptor Antibodies in Pediatric Kidney Transplant Recipients

了解 Allo 和自身免疫的界面：血管紧张素 II 1 型受体抗体对儿童肾移植受者的影响

• 批准号: 10662392
• 负责人: Meghan Haley Pearl
• 金额: $ 20.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662392
• 关键词: Acute; Adult; Allografting; Angiotensin Receptor; Angiotensins; Antibodies; Area; Arteritis; Autoantibodies; Autoimmunity; Award; Biometry; Biopsy; Biopsy Specimen; Blood specimen; California; Child; Childhood; Chronic Kidney Failure; Circulation; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Design; Data; Development; Development Plans; Dialysis procedure; Doctor of Philosophy; End stage renal failure; Endothelial Cells; Extracellular Signal Regulated Kinases; Fc Receptor; Fellowship; Foundations; Frequencies; Functional disorder; Funding; Future; G-Protein-Coupled Receptors; Gene Modified; Goals; HLA Antigens; High Prevalence; Hypertension; IL8 gene; Immunofluorescence Immunologic; Immunogenetics; Immunologic Monitoring; Immunologics; Inflammatory; Injury; Interleukin-1 beta; Interleukin-6; Isoantibodies; Kidney Transplantation; Longitudinal Studies; Los Angeles; Losartan; Master of Science; Measures; Mediating; Mediator; Medicine; Mentorship; Molecular; Molecular Profiling; Nephrology; Odds Ratio; Organ Transplantation; Outcome; PECAM1 gene; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Phosphorylation; Physicians; Pilot Projects; Population; Process; Publishing; Quality of life; Receptor, Angiotensin, Type 1; Renal function; Research; Role; Sampling; Scientist; Serum; Severities; Signal Pathway; Signal Transduction; Stains; Study models; TNF gene; Testing; Therapeutic Agents; Thromboplastin; Time; Tissues; Training; Training Programs; Transplant Recipients; Transplantation; Transplantation Immunology; Universities; Vulnerable Populations; Work; antibody-mediated rejection; career; career development; cohort; cytokine; donor-specific antibody; education planning; improved; in vivo; kidney allograft; laboratory experience; medical schools; novel strategies; novel therapeutics; pediatric patients; post-transplant; professor; renal damage; risk stratification; skills; study population; success; synergism; targeted treatment; transcriptome; treatment choice; vascular inflammation; vascular injury

PROJECT SUMMARY/ABSTRACT This proposal outlines a 5-year career development plan for Meghan Pearl, MD, an Assistant Professor in the Division of Pediatric Nephrology at the David Geffen School of Medicine, University of California, Los Angeles (UCLA). Dr. Pearl recently completed her fellowship in Pediatric Nephrology at UCLA and is highly motivated to be starting a career in academic medicine. She has recently obtained a Master of Science in Clinical Research (degree awarded June 2018) which will provide the ideal foundation for her proposed additional training. She will benefit from the superior mentorship of Elaine F Reed, PhD, a world renowned leader in Immunogenetics and Transplant Immunology. Under Dr. Reed’s guidance, Dr. Pearl will complete essential training objectives which will provide the groundwork for success in achieving her long term goal of becoming an independent clinical investigator. At the core of her training program will be 1) completing essential training in transplant immunology through formal coursework and laboratory experience, 2) expanding her statistical skills through intensive training in computational biostatistics, and 3) acquiring advanced expertise in clinical trial design, conduct, and management. This education plan will result in the acquisition of the necessary skills to become an independent physician scientist in transplantation and successfully compete for R01 funding. Dr. Pearl’s training objectives will be seamlessly integrated with her proposed research, which is focused on the clinical impact and pathophysiology of angiotensin II type 1 receptor antibody (AT1R-Ab) in pediatric kidney transplant recipients (KTRs). In her pilot study, Dr. Pearl found that the post-transplant development of AT1R- Ab, an autoantibody, is significantly more prevalent in pediatric vs. adult KTRs and is associated with allograft loss and decline in renal function in the first 2 years post-transplant1. The overarching goal of this research is to identify patterns of AT1R-Ab mediated allograft injury in pediatric KTRs in the first 5 years post-transplant. We hypothesize that AT1R-Ab mediates vascular inflammation in the allograft leading to decline in renal function and allograft loss in the first 5 years post-transplant. We further hypothesize that AT1R-Ab activates endothelial cells within the allograft resulting in unique molecular signatures associated with allograft injury and loss. This study will not only enrich our understanding of AT1R-Ab pathogenesis, but also serve as a model for the study of non-HLA antibody mediated allograft injury – an area that is currently very poorly understood. Pediatric KTRs will have the most to benefit from this work given 1) the high frequency of AT1R-Ab in this population and 2) their vulnerability to immunologic complications as a result of the need for repeated transplantation over their lifetimes. This study will help determine the utility of AT1R-Ab testing in immunologic risk stratification of KTRs and the potential impact of proactive, targeted treatment on renal allograft survival, and therefore, patient survival and quality of life.

项目总结/摘要 该提案概述了梅根珍珠，医学博士，在助理教授5年的职业发展计划 洛杉矶加州大学大卫格芬医学院儿科肾脏病学分部 （UCLA）。Pearl博士最近完成了她在加州大学洛杉矶分校的儿科肾脏学研究， 开始学术医学生涯她最近获得了临床医学硕士学位， 研究（学位授予2018年6月），这将为她提出的额外的理想基础 训练她将受益于伊莱恩F里德，博士，世界知名的领导者，在上级指导。 免疫遗传学和移植免疫学。在Reed博士的指导下Pearl博士将完成 培训目标，这将为成功实现她的长期目标奠定基础， 独立的临床研究者。她的训练计划的核心是：1）完成基本训练 在移植免疫学通过正式的课程和实验室经验，2）扩大她的统计 技能，通过密集的培训，在计算生物统计学，和3）获得先进的专业知识，在临床 试验设计、实施和管理。这一教育计划将导致获得必要的技能 成为一名独立的移植医生科学家，并成功地竞争R 01基金。 博士珀尔的培训目标将与她提出的研究无缝结合，重点是 血管紧张素II 1型受体抗体（AT 1 R-Ab）在小儿肾脏中的临床影响和病理生理学 移植受体（KTRs）。在她的初步研究中，Pearl博士发现，移植后AT 1 R的发展- Ab是一种自身抗体，在儿童KTR中比成人KTR明显更普遍，并与同种异体移植物相关 移植后前2年肾功能丧失和下降1。这项研究的首要目标是 确定移植后前5年内AT 1 R-Ab介导的儿科KTR同种异体移植物损伤的模式。 我们假设AT 1 R-Ab介导了同种异体移植物中的血管炎症，导致肾功能下降。 移植后前5年的功能和同种异体移植物丢失。我们进一步假设AT 1 R-Ab激活 同种异体移植物内的内皮细胞导致与同种异体移植物损伤相关的独特分子特征， 损失本研究不仅丰富了我们对AT 1 R-Ab发病机制的认识，而且也为AT 1 R-Ab的治疗提供了一个模型。 非HLA抗体介导的同种异体移植物损伤的研究--这一领域目前还知之甚少。 考虑到1）AT 1 R-Ab在这一研究中的高频率， 2）由于需要重复接种， 移植在他们的生命中。这项研究将有助于确定AT 1 R-Ab检测在免疫学中的实用性。 KTR的风险分层以及前瞻性靶向治疗对肾移植存活率的潜在影响， 从而提高患者的生存率和生活质量。

项目成果

Long term tolerability and clinical outcomes associated with tocilizumab in the treatment of refractory antibody mediated rejection (AMR) in pediatric renal transplant recipients.

• DOI: 10.1111/ctr.14734
• 发表时间: 2022-08
• 期刊: CLINICAL TRANSPLANTATION
• 影响因子: 2.1
• 作者: Pearl, Meghan;Weng, Patricia L.;Chen, Lucia;Dokras, Aditi;Pizzo, Helen;Garrison, Jonathan;Butler, Carrie;Zhang, Jennifer;Reed, Elaine F.;Kim, Irene K.;Choi, Jua;Haas, Mark;Zhang, Xiaohai;Vo, Ashley;Chambers, Eileen Tsai;Ettenger, Robert;Jordan, Stanley;Puliyanda, Dechu
• 通讯作者: Puliyanda, Dechu