Expression of Epstein–Barr Virus–Encoded Small RNA (by the EBER-1 Gene) in Liver Specimens from Transplant Recipients with Post-Transplantation Lymphoproliferative Disease

Abstract

Epstein-Barr virus (EBV)—associated post-transplantation lymphoproliferative disease (PTLD) develops in 1 to 10 percent of transplant recipients, in whom it can be treated by a reduction in the level of immunosuppression. We postulated that the tissue expression of the small RNA transcribed by the EBER-1 gene during latent EBV infection would identify patients at risk for PTLD. We studied EBER-1 gene expression in liver specimens obtained from 24 patients 2 days to 22 months before the development of PTLD, using in situ hybridization with an oligonucleotide probe. Control specimens were obtained from 20 recipients of allografts with signs of injury due to organ retrieval, acute graft rejection, or viral hepatitis in whom PTLD had not developed 9 to 71 months after the biopsy. Of the 24 patients with PTLD, 17 (71 percent) had specimens in which 1 to 40 percent of mononuclear cells were positive for the EBER-1 gene. In addition, 10 of these 17 patients (59 percent) had specimens with histopathological changes suggestive of EBV hepatitis. In every case, EBER-1—positive cells were found within the lymphoproliferative lesions identified at autopsy. Only 2 of the 20 controls (10 percent) had specimens with EBER-1—positive cells (P<0.001), and such cells were rare. EBER-1 gene expression in liver tissue precedes the occurrence of clinical and histologic PTLD. The possibility of identifying patients at risk by the method we describe here and preventing the occurrence of PTLD by a timely reduction of immunosuppression needs to be addressed by future prospective studies. (N Engl J Med 1992;327:1710–4.), POST-TRANSPLANTATION lymphoproliferative disease (PTLD), either polyclonal or monoclonal, complicates the clinical course of 1 to 10 percent of organ-transplant recipients.123 Immunohistochemical studies have demonstrated that the lymphoid cells within the lesions of PTLD almost invariably contain Epstein–Barr virus (EBV), primarily in a state of latent infection.4,5 The EBER-1 gene is expressed early during latent EBV infection and codes for a small messenger RNA (mRNA) expressed at up to 107 copies per cell.6 We and others have previously demonstrated the value of the detection of EBER-1 RNA for identifying EBV-infected cells in formalin-fixed paraffin-embedded tissues.7,8 In the current investigation, we used… © 1992, Massachusetts Medical Society. All rights reserved