? Despite advances in medical and gene therapy, orthotopic liver transplantation remains the only definitive therapeutic option for children with end-stage liver disease and certain metabolic disorders. Recent advances in pre-, intra-and early post-transplant care have resulted in a dramatic improvement in survival of the pediatric liver transplant patient. The broad long-range goal of our research program is directed at enhancing the patients' long-term survival. Our primary focus relates to obligate life-long immunosuppression, with its inherent complications including severe infection and development of cancer. These two complications come together in a single disease, Epstein-Barr Virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD). EBV, a latent human lymphotrophic herpes virus infects and immortalizes human B cells. Primary infection usually occurs via salivary exchange and results in a mild, self-limiting illness (infectious mononucleosis) followed by life-long EBV-specific T cell controlled EBV latency. T-cell based immunosuppression prevents allograft rejection, however, it also suppresses cytotoxic T lymphocyte (CTL) function generating an environment in which EBV-infected B cells can proliferate. Patients receiving life-long T cell based immunosuppression have an increased risk of developing PTLD due to their inability to produce normal immunoregulatory responses. Studies have suggested that EBV load and maintenance of host immunoregulation may be an important indicator of PTLD development. This disease is particularly devastating to the pediatric patient as its incidence is at least 4-fold greater than in the adult liver transplant-patient population. In fact, PTLD is the number one cause of death following pediatric liver transplantation. At this time, there is no definitive method of prospectively detecting, diagnosing, or treating PTLD, and current treatment protocols place the liver allograft and patient at risk. Therefore, a diagnostic tool that is both sensitive and specific, and a treatment strategy with low toxicity are greatly needed to decrease the morbidity and mortality suffered by the pediatric liver transplant patient with PTLD. The investigation proposed herein involves studies that will support our hypothesis that the combination of a persistently elevated EBV load in the setting of a diminished immune response to EBV will be an early risk indicator associated with PTLD development, and that pre-emptive treatment utilizing autologous adoptive EBV-specific CTL immunotherapy will provide a low toxicity treatment option. The specific experimental goals proposed include:
Specific Aim 1 : To identify pediatric liver transplant recipients with persistently high EBV levels who fail to mount an adequate immune response to EBV, and Specific Aim 2: To determine if infusions of autologous EBV-specific CTL lines are safe, increase immunity to EBV and reduce viral burden in pediatric liver transplant recipients. We plan to serially follow our pediatric liver transplant recipients monthly following transplantation with real time quantitative DNA analysis for EBV load and antiviral immunity via EBV-specific ELISPOT assays. In patients found to have persistently high loads of EBV and a diminished level of EBV-specific immunity, despite minimization of T-cell based immunosuppressive medications, EBV-specific CTLs will be generated and administered in a phase 1 dose escalation study. These studies represent a phase 1 trial to determine the relevance of EBV load and EBV-specific immune responses following liver transplantation. In addition, these studies will determine the safety and ability of autologous adoptive EBV-specific CTL immunotherapy to enhance EBV-specific immunocompetency. The data from our proposed study will provide the database for the development of future larger multi-centered trials to determine the utility of this adoptive immunotherapeutic regimen ? ?
| Lee, Timothy C; Savoldo, Barbara; Barshes, Neal R et al. (2006) Use of cytokine polymorphisms and Epstein-Barr virus viral load to predict development of post-transplant lymphoproliferative disorder in paediatric liver transplant recipients. Clin Transplant 20:389-93 |
| Lee, Timothy C; Goss, John A; Rooney, Cliona M et al. (2006) Quantification of a low cellular immune response to aid in identification of pediatric liver transplant recipients at high-risk for EBV infection. Clin Transplant 20:689-94 |
| Lee, Timothy C; Savoldo, Barbara; Rooney, Cliona M et al. (2005) Quantitative EBV viral loads and immunosuppression alterations can decrease PTLD incidence in pediatric liver transplant recipients. Am J Transplant 5:2222-8 |
| Savoldo, Barbara; Rooney, Cliona M; Quiros-Tejeira, Ruben E et al. (2005) Cellular immunity to Epstein-Barr virus in liver transplant recipients treated with rituximab for post-transplant lymphoproliferative disease. Am J Transplant 5:566-72 |
