Transplant EBV Disease: Pathogenesis and Immunotherapy

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Immunosuppressive therapies used in pediatric solid organ transplantation are associated with the development of Epstein-Barr virus (EBV) driven lymphoproliferative disease. (PTLD) Almost one in 10 pediatric heart transplant (Tx) recipients will develop PTLD by 7 years after Tx. Long-term outcomes of patients with this complication have been disappointing. Ninety percent of cases are driven by EBV and almost all tumors are of recipient B cell origin. A majority ot Tx patients develop persistently elevated viral loads and we do not have a clear understanding of how these loads are established or maintained, or a clear picture of what dangers persistent viral loads represent to an asymptomatic carder. We propose a virologic analysis of persistent EBV infection in the pediatric heart (H) and heart/lung (H/L) Tx recipients at the Children's Hospital of Pittsburgh. For this study, we plan to use quantitative PCR and immunohistochemical techniques to characterize the high and low viral load in terms of the B cell compartments involved, the degree of clonality of the virus infected cells, and the patterns of viral promoter usage and gene expression. By using an existing specimen bank, to which we will add during the study, data will be collected retrospectively and prospectively to provide a clear picture of the course of virus infection that leads to the load carder state and PTLD. Impaired T cell immune surveillance is an important correlate in progressionto chronic high viral loads and PTLD, and little is known about the residual responder cell types in terms of their frequencies and specificities in immunosuppressed Tx patients. Preliminary work indicates that T cell responses may be skewed away from the beneficial Th1 phenotype towards the less effective Th2 phenotype. Using HLA-tetramer and ELISPOT assays we will characterize the repertoire and frequency of anti-EBV CD8 T cell responses in H and H/L Tx patients. The management of patients with EBV disease, in general, and PTLD in particular remains extremely challenging despite a number of advances in the care of these patients. While many, if not the majority of patients will experience a clinical response to reduction of immune suppression, this is done at the potential cost of developing superimposed rejection during thistherapeutic manipulation. For H or HtL Tx recipients, acceptance of this risk of rejection must come with the knowledge that rejection may present with dysrhythmia and sudden death. We will develop adoptive immunotherapy with EBV-specific CTLs as a safe and effective alternative therapy for pediatric H and H/L Tx recipients. A phase 1 clinical trial will be conducted to determine the response of fractory PTLD, relapsed PTLD, or symptomatic EBV disease in pediatric thoracic Tx recipients to infusions of CTLs raised against specific EBV antigens using dendritic cells.