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Topic Overview:

Post-transplantation lymphoproliferative disorders (PTLD) represent a wide range of malignant tumors that are a feared and often fatal complication of solid organ transplantation. Caused by primary or reactivated infection with Epstein-Barr virus (EBV) and chronic immunosuppression, PTLD disproportionately strikes up to 10 percent of pediatric patients, usually within one to two years after transplantation. There is no single or definitive cure for PTLD; thus, early detection and prevention remain the focus of investigation.

In her research on PTLD in pediatric heart transplant recipients, Dr. Metes uses a two-pronged approach. Her first goal has been to characterize T cell immunologic profiles in an effort to identify those patients at highest risk of progression toward PTLD. Although serial viral load monitoring can identify a subset of pediatric transplant patients with persistently high EBV loads in the bloodstream, the technique is not specific for predicting which of these children will subsequently develop PTLD. Dr. Metes performed flow cytometric analyses and immune cell function assays on peripheral blood samples obtained from pediatric heart transplant patients who were either well-controlled with EBV infection, high-load EBV carriers, or affected by PTLD. Her results demonstrate distinct phenotypic and functional signatures of EBV-specific T cells among these groups, holding promise for the development of novel prognostic biomarkers that may lead to earlier detection of patients at high risk of PTLD, earlier therapeutic intervention, and possibly improved outcomes.

Dr. Metes’ second major research aim is to generate a protocol for the in vitro expansion of a transplant patient’s own EBV-specific T cells, “rescuing” them from an immunosuppressed state and reinfusing them into the patient as potent killers of PTLD tumor cells. Her work has shown that lymphocytes extracted from pediatric transplant patients, presented with EBV-antigen- loaded dendritic cells and supplemented with pro-inflammatory cytokines, can indeed be primed or reactivated into effective cytotoxic anti-EBV T cells. Next steps are underway to expand the scale of EBV-specific T cell polarization and to conduct initial clinical trials. Dr. Metes’ work on selective cellular immunotherapy may well lead to a valuable treatment modality to restore cellular immunity, control EBV load, and eliminate tumor burden in patients with PTLD.

As a multidisciplinary, collaborative effort involving immunology, virology, and genetics, Dr. Metes’ research is funded through grants from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Roche Organ Transplantation Research Foundation; and the Thomas E. Starzl Transplantation Institute.