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: 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
• 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

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)： 免疫抑制和外科治疗的进展改善了肝移植受者的短期患者和移植物存活率，但也给我们留下了不同的挑战：维持同种异体移植物的功能，同时将与免疫抑制药物相关的长期免疫和非免疫并发症降至最低。可以说，这对那些面临长寿命的儿童来说是最重要的，因此，他们更有可能发生严重的同种异体移植和其他末端器官损伤。目前的建议通过评估在定义明确的儿科肝移植受者群体中停用免疫抑制药物的有效性和安全性来应对这一挑战，这些受者的固有免疫状态可能倾向于手术耐受。这项建议汇集了来自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)一个在儿科肝移植方面具有丰富经验的数据协调中心。这个经验丰富且卓有成效的研究联盟的目标是，在U34计划期间，最终敲定临床试验方案的所有方面和相关的翻译研究，从而确保未来快速而顺利地启动试验。随着U34任期内特定任务的完成，即将到来的临床试验的目标将是： (1)对肝移植后超过48个月、移植肝功能和组织学正常的儿童进行一项多中心随机对照试验，以确定在总体上可接受的撤药失败率，特别是同种异体排斥反应的情况下，是否可以安全地撤除免疫抑制剂。如果患者达到手术耐受性，即在没有所有免疫抑制的情况下，通过肝脏测试评估至少12个月的正常同种异体肝移植功能，则将被认为是成功的。 (2)：应用外周血流式细胞术和转录水平评估，获得儿童肝移植受体手术耐受性的预测生物标志物。假设外周血细胞表型和转录图谱将预测手术耐受性，并提示前耐受性机制。 (3)。确定通过T细胞记忆标记物评估的免疫成熟度和T细胞对病毒病原体反应的定量评估与预测IS戒断结果的生物标记物的准确性和稳定性之间的关系。假说是，与暴露于环境病原体产生的扩张性T细胞记忆谱系相比，耐受性良好的生物标志物表型在有限的受者中更为常见。 这项试验将建议进行诊断性研究，以确定对哪些患者来说停用免疫抑制是安全的，阐明保护性免疫与同种异体反应之间的关系，并揭示儿童肝移植受者自发手术耐受的机制。