Biliary Atresia Clinical Research Consortium

描述(由申请人提供)： 胆道闭锁(BA)是一种病因不明的疾病，如果不诊断，几乎所有人都会死亡。即使有了诊断和适当的治疗，与BA相关的发病率也很高。在美国，每年有250-400名患者被诊断为这种疾病。这些患者中约有60%-80%将发展为终末期肝病，需要肝移植。目前，BA是美国儿童肝移植的主要适应症。缺乏全国性的研究和治疗这些患者的网络大大损害了临床和研究的进步，因为每个单独的中心看到的BA患者相对较少。因此，关于基本问题的数据很少，这些问题可能从根本上改变这些患者的结局，例如病因、诊断技术、内科和外科治疗以及移植后治疗。全国性胆道闭锁临床研究联盟(BACRC)的成立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德克萨斯儿童医院(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，在BACRC登记和护理患者。德克萨斯儿童肝脏中心通过综合医疗、外科和移植人员的参与，为患有肝病的儿童提供全面的服务和协调的护理方法。德克萨斯儿童肝脏中心建议在此应用程序中解决BA患者的3个方面的需求：1)开发一个数据库，以收集相关的患者数据，并加强对BACRC的参与；通过确定患有偏侧缺陷的BA患者是否存在Inversin(InVS)基因突变来探索BA的潜在病因；以及3.探索一种新的治疗方法，包括输注患者来源的针对EB病毒(EBV)的细胞毒性T淋巴细胞(CTL)细胞系，以治疗最具破坏性的移植后结果，这种结果优先发生在儿科移植受者：移植后淋巴增殖性疾病(PTLD)。自体输注EBV特异性CTL株可以恢复EBV转化的B细胞的免疫调节的自然平衡，这种平衡被当前基于T细胞的免疫抑制的固有性质所抑制。IRB、FDA和NIH批准的这种治疗方案目前正在TCH实施，并得到综合临床研究中心的支持。 只有通过参与全国性的多机构方法，我们才能开始发现信息，以了解和治疗像BA这样有终身需求的患者。

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.