Biliary Atresia Clinical Research Consortium

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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.