Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients

稳定儿童肝移植受者的免疫抑制撤药

• 批准号: 8334913
• 负责人: Sandy Feng
• 金额: $ 5.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334913
• 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; Cytomegalovirus; Data; Data Analyses; 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; IL2RA gene; Immune; Immune Tolerance; Immunity; Immunologic Monitoring; Immunologics; Immunology; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Institutional Review Boards; Intervention; Left; Lipids; Liver; Living Donors; Longevity; Major Histocompatibility Complex; Memory; Microarray Analysis; Microfluidics; Monitor; Morbidity - disease rate; Motivation; National Institute of Allergy and Infectious Disease; 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; 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; 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

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提高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。这对于那些寿命长的儿童来说是最重要的，因此，更有可能发生重大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在明确定义的儿童肝移植受者人群中停用免疫抑制剂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易导致手术耐受。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学（2）移植免疫学，（3）移植组织病理学和（4）在儿科肝移植方面具有丰富经验的数据协调中心。这个经验丰富、成就卓著的研究联盟旨在U34计划期间，最终确定临床试验方案和相关转化研究的各个方面，从而确保未来快速、顺利地启动试验。在U34任期内完成指定任务后，即将进行的临床试验的目标将是： (1)在肝移植术后超过48个月且移植物功能和组织学正常的儿童中进行一项免疫抑制剂撤药的多中心随机对照试验，以确定是否可以安全地进行免疫抑制剂撤药，一般撤药失败率和特别是同种异体移植物排斥反应率可接受。如果患者达到手术耐受，即在不存在所有免疫抑制的情况下，至少12个月通过肝脏检查评估的正常肝移植功能，则认为退出成功。 (2)利用外周血流式细胞术和转录评估推导出小儿肝移植受者手术耐受性的预测性生物标志物。该假说是外周血细胞表型和转录谱将预测操作耐受性，并提出亲耐受机制。 （三）、确定免疫成熟度（通过T细胞记忆标志物和T细胞对病毒病原体反应的定量评估进行评估）与预测IS戒断结局的生物标志物准确性和稳定性之间的关系。该假设是，亲耐受生物标志物表型在具有有限的与通过暴露于环境病原体而产生的扩展的T细胞记忆库相比的受体中将更常见。 本试验将建议进行诊断性研究，以确定免疫抑制停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，并揭示小儿肝移植受者自发手术耐受的机制。