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

项目摘要/摘要 实体器官移植是目前治疗各种终末期儿童的首选方法 器官疾病。临床移植的成功取决于强效药物的使用。 预防同种异体移植排斥反应的免疫抑制药物。然而，即使有我们的武器库 免疫抑制剂，10%-40%的儿科移植受者会出现排斥反应 发病发生在移植后第一年。显然，急性排斥反应仍然是儿科固体治疗的主要障碍。 因此，器官移植是拟议的机制研究中要解决的关键问题。 CTOT-C《儿童移植后淋巴增生性疾病的生物标志物》将入选 1000名儿童肝、心、肾或肠移植受者和数千名个体血液 样本将被收集、处理(全血、PBMC和血浆)并储存在斯坦福大学。在这 提案中，独特的CTOTC-06样本队列、临床数据和已建立的基础设施将是 用于识别新的和强大的同种异体移植状态的替代终点。在初步研究中，我们有 已识别的与急性排斥或稳定移植相关的microRNA和细胞表型 功能。我们现在建议测定外切体miRNome，分析TCR和免疫球蛋白Heavy 链式库，并用质量细胞术对同种异体免疫反应进行多参数分析 为了确定肝移植受者移植功能稳定和急性排斥的生物标志物， 心脏、肾脏和肠道移植。我们假设我们可以识别独特的细胞，分子， 以及免疫反应中与移植结果相关并预测移植结果的功能变化。 我们将在以下具体目标中检验这一假设： 目的1：确定同种异体移植物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来确定同种异体移植物的状态。 开发新的和强大的同种异体移植状态的替代终点将是 儿童实体器官移植领域。

PROJECT SUMMARY/ABSTRACT 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 immunosuppressive drugs to prevent rejection of the allograft. However, even with our arsenal of immunosuppressive 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.