Biliary Atresia Clinical Research Consortium

胆道闭锁临床研究联盟

• 批准号: 6548923
• 负责人: SAUL J. KARPEN
• 金额: $ 22.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-07 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548923
• 关键词: Epstein Barr virus; artificial immunosuppression; biliary atresia; children; clinical research; cooperative study; cytotoxic T lymphocyte; gene mutation; genetic regulation; human subject; human therapy evaluation; immunotherapy; liver transplantation; patient /disease registry; patient oriented research; postoperative complications

DESCRIPTION (provided by applicant): Biliary atresia (BA) is a disease of unknown etiology that, if undiagnosed leads almost universally to death. Even with diagnosis and appropriate treatment, there is tremendous morbidity associated with BA. There are 250-400 patients diagnosed annually with this disorder in the United States. Approximately 60-80% of these patients will develop end-stage liver disease, and will require liver transplantation. Currently, BA is the main indication for liver transplantation in children in the United States. The lack of a nationwide network to study and treat these patients significantly impairs clinical and research advancements, since each individual center sees relatively few BA patients. As a consequence, there are few data about basic issues, which could fundamentally change the outcome for these patients, e.g., etiology, diagnostic techniques, medical and surgical management, and post-transplantation therapy. The formation of a nationwide Biliary Atresia Clinical Research Consortium (BACRC) will allow such data to be collected, leading to improved outcomes for BA patients nationwide. At the Texas Children's Hospital (TCH), the largest pediatric hospital in the United States, we propose to use the resources of the institution and the dedicated Texas Children's Liver Center to enroll and care for patients in the BACRC. The Texas Children's Liver Center provides a full-service and coordinated approach to the care of children with liver disease, by synthesizing the involvement of medical, surgical, and transplant personnel. There are 3 areas of need of BA patients that the Texas Children's Liver Center proposes to address in this application: 1.) develop a database to gather relevant patient data and enhance participation in the BACRC;2.) explore an underlying etiology of BA by determining if BA patients with laterality defects have mutations in the lnversin (Invs) gene; and 3.) explore a novel treatment involving infusion of patient-derived cytotoxic T lymphocyte (CTL) cell lines directed against Epstein Barr Virus (EBV) for the most devastating of post-transplant outcomes that preferentially occurs in pediatric transplant recipients: Post-Transplant Lymphoproliferative Disorder (PTLD). Autologous infusion of EBV-specific CTL lines may restore the natural balance of immunomodulation of EBV-transformed B cells that is suppressed by the inherent nature of current T-cell based immunosuppression. An IRB, FDA, and NIH-approved protocol for this therapy is currently in place at the TCH and involves the support of the General Clinical Research Center. It is only by engaging in a nationwide multi-institutional approach that we can begin to discover information to understand and treat patients with life-long needs like BA.

描述（由申请人提供）： 胆道闭锁（BA）是一种未知病因的疾病，如果未诊断的疾病几乎普遍导致死亡。即使进行诊断和适当的治疗，BA也有很大的发病率。在美国，每年有250-400名患者患有这种疾病。这些患者中约有60-80％将发展终末期肝病，需要肝移植。目前，BA是美国儿童肝移植的主要指标。由于每个中心的BA患者相对较少，因此缺乏研究和治疗这些患者的全国性网络会严重损害临床和研究进步。结果，关于基本问题的数据很少，这些数据从根本上可以改变这些患者的结果，例如病因，诊断技术，医疗和手术管理以及移植后治疗。全国胆道闭锁临床研究联盟（BACRC）的形成将允许收集此类数据，从而改善全国BA患者的预后。在美国最大的儿科医院得克萨斯州儿童医院（TCH），我们建议利用该机构和专门的德克萨斯儿童肝脏中心的资源来招募和护理BACRC患者。德克萨斯州儿童肝脏中心通过综合医疗，外科和移植人员的参与，为护理肝病儿童提供全方位服务和协调的方法。德克萨斯儿童肝脏中心提议在本应用程序中提出的解决方案有3个需要：1。）开发一个数据库来收集相关患者数据并增强BACRC的参与； 2。）探索BA的潜在病因，通过确定BA侧向患者的侧向缺陷是否在LNVersin（Invs）（Invs Invs）基因中进行突变。和3.）探索一种新的治疗方法，涉及针对Epstein Barr病毒（EBV）注入患者衍生的细胞毒性T淋巴细胞（CTL）细胞系，以使移植后结局最毁灭性，这些结果优先发生在儿科移植中：后植物植物淋巴结型症状障碍（PTLANTPLANT）。自体输注EBV特异性CTL系可能会恢复EBV转换B细胞免疫调节的自然平衡，而EBV转化的B细胞受到当前基于T细胞的免疫抑制的固有性质的抑制。目前，TCH已制定了该疗法的IRB，FDA和NIH批准的方案，并涉及一般临床研究中心的支持。 只有从事全国性的多机构方法，我们才能开始发现信息以理解和治疗诸如BA之类的终身需求的患者。