Evidence for restricted Epstein-Barr virus latent gene expression and anti-EBNA antibody response in solid organ transplant recipients with posttransplant lymphoproliferative disorders

Abstract

Epstein-Barr virus (EBV) is associated with the development of two human B-cell malignancies, Burkitt's lymphoma and lymphomas that occur in the immunosuppressed host. The latter category of disease has become important recently as it is seen primarily in organ transplant recipients and individuals with acquired immunodeficiency syndrome. One possible mechanism for lymphoma development involves a reduction in or lack of EBV-specific cytotoxic T-cell recognition. In support of this model are previous observations that the expression of EBV nuclear antigen 2 (EBNA2) and latent membrane protein, two viral antigens associated with major histocompatibility complex class I-restricted T- cell killing, are downregulated in Burkitt's lymphoma and in early passage lymphoblastoid cell lines (LCL) derived from the malignant lesions. To determine whether a similar mechanism could occur in the development of posttransplant lymphoproliferative disorders (PTLD), we compared EBV gene expression among 23 PTLD tumor lesions obtained from 11 solid organ transplant recipients and among LCL derived from 3 of these lesions. In this report, we demonstrate, by Southern blot, Western blot, and immunofluorescence analysis, that (1) the tumor lesions exhibit varying patterns of restricted viral gene expression; (2) LCL derived from these lesions may represent the in vitro selection of cell subpopulations; and (3) immunosuppressed individuals have a markedly reduced antibody response to the latent cycle antigens, EBNA1, EBNA2, and EBNA-LP, but not to the lytic cycle viral capsid antigen when compared with normal immunocompetent controls.

In vitro EBV-infected subline of KMH2, derived from Hodgkin lymphoma, expresses only EBNA-1, while CD40 ligand and IL-4 induce LMP-1 but not EBNA-2

“…30,31 Although further experiments are needed to provide direct evidence, it is tempting to speculate that the lack of BSAP and Oct-2 might be the reason why type III latency with EBNA-2-6 expression is not induced in the KMH2 EBV cells. It is likely that the same condition determines the silence of Wp/Cp in other EBV-carrying lymphomas with a postgerminal center (post-GC) phenotype, such as cells in posttransplant lymphoproliferative disease (PTLD), 32,33 the rare EBV-positive plasmacytomas, 34 pleural effusion lymphomas (body cavity lymphomas) 35,36 and plasmablastic lymphomas of the oral cavity. 37 Requirement for the B-cell phenotype for type III EBV latency was first shown in experiments with somatic cell hybrids, since only those hybrids that maintained the B-cell phenotype, provided by one of the partners, maintained the type III latency.…”

Posttransplantation lymphoproliferative disorder in liver recipients: Characteristics, management, and outcome

“…It is strongly associated with recent EBV infection. 7,10,[20][21][22][23][24][25][26] In immunosuppressed patients, PTLD is believed to result from inadequate T-cell control over EBVdriven B-cell proliferation. 2 Data from EBV in situ hybridization studies have been previously reported [22][23][24][25] , 19 of the 20 cases analyzed had positive EBV hybridization findings.…”

“…7 A particularly close association has been noted after therapy with the monoclonal antibody OKT3, 8,9 and the Epstein-Barr virus (EBV) is believed to have an important etiologic role in the development of PTLD. 7,10 The malignant lymphomas typically behave in a very aggressive fashion, with a far greater incidence of extranodal presentation and invasion of the central nervous system, a lesser likelihood of response to conventional lymphoma therapies, and poorer outcome than lymphomas in nontransplanted patients. 11 In light of these differences and the apparently greater incidence of PTLD in liver transplant recipients, we examined the clinical characteristics, course, and therapeutic outcome of PTLD in liver transplant recipients.…”

CD4+ T‐cell responses to Epstein–Barr virus (EBV) latent membrane protein 1 in infectious mononucleosis and EBV‐associated non‐Hodgkin lymphoma: Th1 in active disease but Tr1 in remission

“…In latent infection gene expression is greatly restricted, with a series of programs expressing 0-10 genes (Kieff & Rickinson, 2001). In NHL, expression of EBV proteins is variable, although a type III latency pattern, which includes LMP1, is common in immunodeficient patients (Cen et al, 1993;Kuze et al, 2000). Thus, LMP1 is expressed in both IM and invasive EBV-driven NHL.…”