Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

稳定儿童肝移植受者的免疫抑制撤药

基本信息

批准号：
7943019
负责人：
Sandy Feng
金额：
$ 45.47万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943019
关键词：
6 year old Abbreviations Acute Address Adrenal Cortex Hormones Adult Adverse event Alanine Transaminase Allograft Tolerance Allografting Antibodies Antigens Area Aspartate Biological Assay Biological Markers Blood Cells Blood Flow Cytometry Blood Pressure Blood specimen Bolus Infusion CD4 Positive T Lymphocytes Calcineurin inhibitor Caring Case Report Form Child Childhood Chronic Climacteric Clinical Clinical Trials Clinical Trials Data Monitoring Committees Clinical trial protocol document Collaborations Communication Confidence Intervals Cyclosporine Cyclosporins Cytomegalovirus Data Data Collection Data Coordinating Center Diagnostic Dose Effectiveness Electronics Ensure Event Exposure to Face Failure Fingerprint Flow Cytometry Frequencies Future Gamma-glutamyl transferase Glomerular Filtration Rate Goals Graft Survival Health Hepatology Histology Histopathology Human Herpesvirus 4 Immune Immune Tolerance Immunity Immunologic Monitoring Immunologics Immunology Immunosuppression Immunosuppressive Agents Individual Infection Intervention Left Lipids Liver Living Donors Longevity Major Histocompatibility Complex Memory Microarray Analysis Microfluidics Monitor Morbidity - disease rate Motivation National Institute of Diabetes and Digestive and Kidney Diseases Observational Study Operative Surgical Procedures Organ Organ Preservation Outcome Pathology Patients Peripheral Blood Mononuclear Cell Personal Satisfaction Pharmaceutical Preparations Phenotype Polymerase Chain Reaction Population Preparation Prevalence Principal Investigator Process Protocols documentation Publishing Quality of life Randomized Controlled Trials Renal function Reporting Research Research Ethics Committees Resources Risk Safety Schedule Specific qualifier value Staining method Stains Surface T cell response T memory cell T-Cell Receptor T-Lymphocyte Tacrolimus Techniques Testing Text Toxic effect Transplant Recipients Transplantation Viral Withdrawal Work abstracting allograft rejection antimicrobial base cost cytokine density experience follow-up glycemic control graft function improved liver allograft liver transplantation mortality pathogen peripheral blood pilot trial response sample collection standard of care success tool translational study

项目摘要

DESCRIPTION (provided by applicant): Advances in immunosuppression and surgical care have improved short term patient and graft survival for liver transplant recipients but left us with different challenges: maintaining allograft function while minimizing the long-term immune and non-immune complications related to immunosuppressive medications. This is arguably most important for children who face a long life span and, consequently, a greater potential to develop significant allograft and other end organ damage. The current proposal addresses this challenge by assessing the effectiveness and safety of immunosuppression withdrawal in a well-defined population of pediatric liver transplant recipients whose inherent immune status may predispose to operational tolerance. This proposal brings together expertise from 4 distinct areas, (1) pediatric transplant hepatology and surgery (2) transplant immunology, (3) transplant histopathology and (4) a data coordinating center with extensive experience in pediatric liver transplantation. This experienced and accomplished research consortium aims, during the U34 planning period, to finalize all facets of a clinical trial protocol and associated translational studies, thereby ensuring rapid and smooth trial initiation in the future. With accomplishment of the specified tasks during the U34 tenure, the goals of the forthcoming clinical trial will be to: (1) Conduct a multi-center randomized controlled trial of immunosuppression withdrawal among children more than 48 months after liver transplantation with normal graft function and histology to determine if immunosuppression withdrawal can be done safely with acceptable rates of withdrawal failure in general and allograft rejection in particular. Withdrawal will be considered successful if patients achieve operational tolerance, defined as normal liver allograft function as assessed by liver tests for at least 12 months in the absence of all immunosuppression. (2): Derive predictive biomarkers of operational tolerance for pediatric liver tx recipients using peripheral blood flow cytometry and transcriptional assessment. The hypothesis is that peripheral blood cell phenotypes and transcriptional profiles will predict operational tolerance and suggest pro-tolerant mechanisms. (3). Determine the relationship between immunologic maturity, as assessed by markers of T cell memory and quantitative assessment of T cell responses to viral pathogens, and biomarker accuracy and stability in predicting the outcome of IS withdrawal. The hypothesis is that pro-tolerant biomarker phenotype will be more common in recipients with a limited compared to an expansive T cell memory repertoire engendered by exposure to environmental pathogens. This trial will suggest diagnostic studies that will identify patients for whom immunosuppression withdrawal is safe, elucidate the relationship between protective immunity and alloresponsiveness, and uncover mechanisms involved in spontaneous operational tolerance for pediatric liver transplant recipients.

描述（由申请人提供）：免疫抑制和外科护理的进步改善了肝移植受者的短期患者和移植物存活率，但给我们带来了不同的挑战：维持同种异体移植物功能，同时最大限度地减少与免疫抑制药物相关的长期免疫和非免疫并发症。这对于面临较长寿命的儿童来说可以说是最重要的，因此更有可能发生严重的同种异体移植和其他终末器官损伤。目前的提案通过评估明确的儿科肝移植受者群体中免疫抑制撤药的有效性和安全性来解决这一挑战，这些受者的固有免疫状态可能容易产生操作耐受性。该提案汇集了来自 4 个不同领域的专业知识，（1）儿科移植肝病学和外科（2）移植免疫学，（3）移植组织病理学和（4）在儿科肝移植方面拥有丰富经验的数据协调中心。这个经验丰富、卓有成效的研究联盟的目标是，在 U34 规划期间，最终确定临床试验方案和相关转化研究的所有方面，从而确保未来试验的快速、顺利启动。随着 U34 任期内指定任务的完成，即将进行的临床试验的目标将是：（1）对肝移植后48个月以上且移植物功能和组织学正常的儿童进行免疫抑制戒断的多中心随机对照试验，以确定免疫抑制戒断是否可以安全进行，一般戒断失败率和同种异体移植排斥率可接受。特别的。如果患者达到操作耐受性（定义为在没有所有免疫抑制的情况下通过肝脏测试评估至少 12 个月的同种异体肝功能正常），则停药将被视为成功。 (2)：使用外周血流式细胞术和转录评估得出儿科肝移植受者操作耐受性的预测生物标志物。假设外周血细胞表型和转录谱将预测操作耐受性并提示促耐受机制。（3）。确定免疫成熟度（通过 T 细胞记忆标记和 T 细胞对病毒病原体反应的定量评估进行评估）与生物标记在预测 IS 戒断结果方面的准确性和稳定性之间的关系。假设认为，与暴露于环境病原体而产生的广泛 T 细胞记忆库相比，亲耐受性生物标志物表型在有限的接受者中更为常见。该试验将提出诊断性研究，以确定免疫抑制撤药对哪些患者是安全的，阐明保护性免疫和同种异体反应之间的关系，并揭示儿童肝移植受者自发操作耐受性的机制。