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

项目概要/抽象专利授权 实体器官移植是目前治疗儿童各种终末期肾病的首选方法， 阶段性器官疾病临床移植的成功依赖于使用有效的 免疫抑制药物以防止同种异体移植物的排斥反应。然而，即使有我们的武器库 免疫抑制剂，10-40%的儿科移植受者将有一个 移植后第一年的排斥反应显然，急性排斥反应仍然是一个主要的 在儿科实体器官移植的障碍，因此是关键问题要解决， 提出的机制研究。CTOT-C“移植后生物标志物 儿童肝脏增生性疾病”将招募1000多名儿童肝脏接受者， 将收集心脏、肾脏或肠移植物和数千份个体血液样本， 处理（全血、PBMC和血浆）并储存在斯坦福大学。在这份提案中， CTOTC-06样本队列、临床数据和已建立的基础设施将用于 确定同种异体移植物状态的新的和可靠的替代终点。在初步研究中， 鉴定了与急性排斥反应或稳定性排斥反应相关的microRNA和细胞表型， 移植物功能我们现在提出确定外泌体miRNome，分析TCR和 免疫球蛋白重链库，并进行多参数分析， 通过质谱细胞术进行同种免疫应答，目的是鉴定稳定移植物的生物标志物 功能和急性排斥反应的接受者的肝脏，心脏，肾脏和肠移植。我们 假设我们可以识别出在细胞中独特的细胞、分子和功能变化， 与移植结果相关并可预测移植结果的免疫应答。我们将测试这个 假设的具体目标如下： 目的1：确定同种异体移植对移植后早期免疫反应的影响。 目的2：建立新的诊断和预测方法，以确定同种异体移植物的状态。 开发新的和可靠的同种异体移植物状态替代终点将是一个主要的 儿科实体器官移植领域的进展。

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.