Epstein-Barr Virus Infections and DNA Hybridization Studies in Posttransplantation Lymphoma and Lymphoproliferative Lesions: The Role of Primary Infection

Abstract

Fourteen patients who developed B cell lymphomas or lymphoproliferative lesions after kidney, liver, heart, or heart-lung transplantation in Pittsburgh during [1981][1982][1983] had active infection with Epstein-Barr virus (EBV) of the primary (six patients), reactivated (seven patients), or chronic (one patient) type. In transplant patients without tumors, the incidence of EBV infection was 30% (39 of 128). Only three of these patients had primary infections. Thus the frequency of active infection was significantly higher in patients with tumors, and patients with primary infections were at greater risk of developing tumors. Five of 13 tumors tested contained EBV nuclear antigen (EBNA) and nine of 11 contained EBV genomes detected by DNA-DNA hybridization with BamHI K, BamHI W, or EcoRI B cloned probes. All EBNA-positive tumors, except one, were also positive by hybridization. Only one tumor was negative for both EBNA and EBV DNA. These data suggest that EBV plays an etiologic role in the development of these lesions.Epstein-Barr virus (EBV) is a human herpesvirus associated with an array of conditions that range from inapparent infection and infectious mononucleosis to lethal lymphoproliferative syndromes, nasopharyngeal carcinoma, Burkitt's lymphoma, and B cell lymphomas in immunocompromised patients [1]. The precise role of the virus in carcinogenesis is unclear, although in Burkitt's lymphoma the importance of viral transformation of infected B lymphocytes and chromosomal translocations has been emphasized [2]. It is even less clear in lymphomas and lymphoproliferative lesions arising in immuno-compromised patients, where the immunopathology may not be uniform and where chromosomal studies are largely lacking.Recently, we reported on the reversibility of lymphomas and lymphoproliferative lesions in a series of 17 transplant patients after reduction of cyclosporine and steroid immunosuppression [3]. In that preliminary report we noted that seven of these patients had evidence of primary EBV infections and eight had evidence of reactivated infection. Six tumors had evidence of EBV nuclear antigen (EBNA) and seven had evidence of EBV DNA by nucleic acid hybridization. [6] reported the results of studies on 19 renal transplant patients who developed lymphoproliferative disorders and lymphomas after transplantation. All the patients except one were receiving azathioprine, prednisone, and antithymocyte globulin. Two of their patients developed primary EBV infection, in six the infection reactivated, and 12 had evidence of EBV DNA in their tumors by hybridization studies. Bieber et al. [7] reported that five of 39 heart transplant recipients receiving cyclosporine, prednisone, and antithymocyte globulin developed lymphomas. Four tumors were positive for EBV DNA by cRNA-DNA filter hybridization, and three patients had serological evidence of EBV infection.We report here evidence for active EBV infection in all of our patients with tumors and a significantly higher frequency of primary infection than found i...

The diagnosis and treatment of posttransplant lymphoproliferative disorders

“…121 Again, rare cases are negative for EBV by these techniques?' 21 Over half of the patient population had other concurrent infections at the time of PTLD diagnosis.…”

“…Ninety-four percent of patients under the age of 18 had primary, rather than reactivation, infection. Ho et al 121 have emphasized the importance of primal}' EBV infection in this disorder. Our results are similar to those in other previously published studies in which the oveIWhelming majority of patients had evidence of EBV infection.…”

Epstein-Barr virus transformation: involvement of latent membrane protein 1-mediated activation of NF-κB

“…For most people, latent infection is innocuous due to constant immune surveillance of infected cells. In contrast, immune-compromised individuals may incur a lymphoproliferative disease due to the lack of a continued immune response to EBV (Hamilton-Dutoit et al, 1991Ho et al, 1985;MacMahon et al, 1991; reviewed in Rickinson and Kie , 1996).…”

Role of Epstein-Barr virus and interleukin 6 in the development of lymphomas of human origin in SCID mice engrafted with human tonsillar mononuclear cells

“…Primary infection with or reactivation of EBV, however, can result in severe disease in immunocompromised individuals. Children with congenital primary immunodeficiences (Virelizier et al, 1978;Purtilo et al, 1982), immunosuppressed allograft organ and bone marrow recipients (Hanto et al, 1982;Cleary et al, 1984;Ho et aL, 1985;Shapiro et al, 1988;Zutter et at., 1988;Swinnen et al, 1990), and patients immunocompromised by human immunodeficiency virus are especially susceptible to EBV-associated malignant and often fatal lymphoproliferation Birx et al, 1986;Hamilton-Dutoit et al, 1991). Furthermore, EBV has been strongly linked to other malignancies, including Burkitt's lymphoma, Hodgkin's and non-Hodgkin's lymphoma, T cell neoplasia, nasopharyngeal carcinoma and hairy leukoplakia (de Th6 et al, 1978;Greenspan et al, 1985;Jones et al, 1988;Young et al, 1988;Harabuchi et al, 1990;Pallesen et al, 1991).…”