Exosomes and the Immune Response in Allograft Outcomes in Pediatric Transplant Recipients

外泌体和儿科移植受者同种异体移植结果中的免疫反应

• 批准号: 10339207
• 负责人: Sheri M. Krams
• 金额: $ 218.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339207
• 关键词: Acute; Address; Allografting; Biological Markers; Blood specimen; COVID-19; Child; Childhood; Clinical; Clinical Data; Convalescence; Cytometry; Development; Disease; Enrollment; Goals; Heart; Heart Transplantation; Heavy-Chain Immunoglobulins; Immune; Immune response; Immunosuppressive Agents; Individual; Infrastructure; Intestines; Kidney; Kidney Transplantation; Liver; Lymphoproliferative Disorders; MicroRNAs; Molecular; Multisystem Inflammatory Syndrome in Children; Organ; Organ Transplantation; Outcome; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Plasma; Process; Sampling; Solid; Surrogate Endpoint; Testing; Transplant Recipients; Transplantation; Whole Blood; acute infection; adaptive immune response; allograft rejection; cohort; exosome; gastrointestinal transplantation; graft function; liver transplantation; novel; novel diagnostics; parent grant; post-transplant; prevent; response; success; surveillance study; treatment choice

PROJECT SUMMARY/ABSTRACT PARENT GRANT Solid organ transplantation is currently the treatment of choice for children with a variety of end- stage organ diseases. The success of clinical transplantation is dependent on the use of potent immune-suppressive drugs to prevent rejection of the allograft. However, even with our arsenal of immune-suppressive agents, between 10-40% of pediatric transplant recipients will have a rejection episode in the first-year post-transplant. Clearly, acute rejection remains a major hurdle in pediatric solid organ transplantation and thus is the critical question to be addressed in the proposed mechanistic study. The CTOT-C “Biomarkers for Post-Transplant Lymphoproliferative Disorders in Children” will enroll over 1000 pediatric recipients of liver, heart, kidney or intestinal grafts and thousands of individual blood samples will be collected, processed (whole blood, PBMC and plasma) and stored at Stanford. In this proposal, the unique CTOTC-06 cohort of samples, clinical data and established infrastructure will be utilized to identify novel and robust surrogate endpoints of allograft status. In preliminary studies we have identified microRNAs and cellular phenotypes that correlate with either acute rejection or stable graft function. We now propose to determine the exosome miRNome, analyze TCR and immunoglobulin heavy chain repertoires, and perform a multi-parameter analysis of the alloimmune response by mass cytometry with the goal of identifying biomarkers of stable graft function and acute rejection in recipients of liver, heart, kidney and intestine transplants. We hypothesize that we can identify unique cellular, molecular, and functional changes in the immune response that are associated with and predictive of graft outcomes. We will test this hypothesis in the following specific aims: Aim 1: Determine the impact of an allograft on the early post-transplant immune response. Aim 2: Establish novel diagnostic and predictive approaches to determine allograft status. The development of novel and robust surrogate endpoints of allograft status will be a major advance in the field of pediatric solid organ transplantation.

项目摘要/摘要父母赠款 固体器官移植目前是针对各种末端的儿童的选择 舞台器官疾病。临床移植的成功取决于使用效力 免疫抑制药物以防止对同种异体移植的排斥。但是，即使有我们的武器库 在免疫抑制剂中，10-40％的小儿移植受者将有一个 移植后第一年的拒绝发作。显然，急性拒绝仍然是主要的 小儿固体器官移植的障碍，因此是要解决的关键问题 提出的机械研究。 CTOT-C“移植后生物标志物 儿童的淋巴增生疾病”将招募1000多名肝脏的儿科接受者， 将收集心脏，肾脏或肠道移植物以及成千上万的单个血液样本， 加工（全血，PBMC和等离子体），并存储在斯坦福大学。在此提案中，独特 CTOTC-06样本，临床数据和已建立的基础设施的队列将用于 确定同种异体状态的新颖和坚固的替代终点。在初步研究中，我们有 鉴定出与急性排斥或稳定相关的microRNA和细胞表型 移植功能。我们现在建议确定外泌体mirname，分析TCR和 免疫球蛋白重链曲目，并对 质量细胞术的同种异体反应，目的是识别稳定移植物的生物标志物 肝脏，心脏，肾脏和肠移植的受体的功能和急性排斥。我们 假设我们可以鉴定出独特的细胞，分子和功能变化 与移植结果相关并预测的免疫反应。我们将测试这个 以下特定目标中的假设： 目标1：确定同种异体移植对早期移植后免疫反应的影响。 目标2：建立新颖的诊断和预测方法来确定同种异体移植状态。 同种异体状态的新颖和强大的替代终点的发展将是主要的 在小儿固体器官移植的领域前进。