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: 10188897
• 负责人: Sheri M. Krams
• 金额: $ 103.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188897
• 关键词: Acute; Address; Aliquot; Allografting; Biological Markers; Blood specimen; Cells; Child; Childhood; Clinical; Clinical Data; Cytometry; Development; Disease; Enrollment; Functional disorder; Goals; Graft Rejection; Heart; Heart Transplantation; Heavy-Chain Immunoglobulins; Immune; Immune response; Immunologic Monitoring; Immunosuppression; Immunosuppressive Agents; Incidence; Individual; Infection; Infrastructure; Intestines; Kidney; Kidney Transplantation; Liver; Living Donors; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; MicroRNAs; Molecular; Organ; Organ Transplantation; Outcome; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Plasma; Process; Risk; Sampling; Solid; Surrogate Endpoint; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; Visit; Whole Blood; allograft rejection; cohort; end stage disease; exosome; experience; gastrointestinal transplantation; graft function; high risk; improved; innovative technologies; liver transplantation; new therapeutic target; novel; novel diagnostics; post-transplant; prevent; response; side effect; success; targeted biomarker; transplant centers; treatment choice

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.

项目概要/摘要 实体器官移植是目前多种终末期儿童的首选治疗方法 器官疾病的临床移植的成功取决于强效药物的使用。 然而，即使我们有免疫抑制药物来防止同种异体移植物的排斥。 免疫抑制剂，10-40% 的儿科移植受者会出现排斥反应 显然，急性排斥反应仍然是儿科实体移植后第一年的主要障碍。 器官移植，因此是拟议的机制研究中要解决的关键问题。 CTOT-C“儿童移植后淋巴增殖性疾病的生物标志物”将招募 1000 名儿科接受者的肝脏、心脏、肾脏或肠道移植物以及数千份个人血液 样本将在斯坦福大学进行收集、处理（全血、PBMC 和血浆）并储存。 根据提案，独特的 CTOTC-06 样本队列、临床数据和已建立的基础设施将 在初步研究中，我们使用该方法来确定同种异体移植物状态的新颖且可靠的替代终点。 鉴定出与急性排斥或稳定移植物相关的 microRNA 和细胞表型 我们现在建议确定外泌体 miRNome，分析 TCR 和免疫球蛋白重。 链库，并通过质量细胞术对同种免疫反应进行多参数分析 以生物标志物识别肝脏受者的稳定移植功能和急性排斥反应为目标， 我们勇敢地说，我们可以识别独特的细胞、分子、 以及与移植结果相关并可预测移植结果的免疫反应的功能变化。 我们将在以下具体目标中检验这一假设： 目标 1：确定同种异体移植物对移植后早期免疫反应的影响。 目标 2：建立新的诊断和预测方法来确定同种异体移植物状态。 同种异体移植状态的新颖且强大的替代终点的开发将是一个重大进步 小儿实体器官移植领域。