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: 7738992
• 负责人: Sandy Feng
• 金额: $ 43.39万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738992
• 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 memory cell; T-Cell Receptor; T-Lymphocyte; Tacrolimus; Techniques; Testing; Text; Toxic effect; Transplant Recipients; Transplantation; Viral; Withdrawal; Work; 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）：