Epstein-Barr virus induced lymphoproliferative tumors in severe combined immunodeficient mice are oligoclonal

Abstract

Severe combined immunodeficient (SCID) mice reconstituted with lymphocytes from Epstein-Barr virus (EBV) negative human donors develop aggressive tumors after the chimeric mice are infected with EBV. The tumors were composed of human B cells that expressed EBV encoded antigens (latent membrane protein and EBV nuclear antigen2). Southern blot analysis of DNA from 16 SCID/hu tumors with human Ig gene probes showed that each tumor contained multiple heavy and light chain gene rearrangements. Ig kappa gene rearrangements were frequent, while clonal lambda gene rearrangements were infrequent. Analysis of EBV terminal repeat sequences indicated two or more fused termini in each tumor, consistent with a multiclonal origin. Linear terminal repeat segments and viral antigens (EA-D and EA-R) associated with EBV replication were not detected in the tumors. High levels of human Igs in the SCID/hu serum were oligoclonal and primarily contained kappa light chains. Before the appearance of overt tumors, circulating cells with human and EBV DNA could be detected in the SCID/hu mice by the polymerase chain reaction. We conclude that EBV infection in SCID/hu chimeric mice produces a limited number of transformation events, which give rise to oligoclonal tumors resembling EBV-associated lymphoproliferative disorders in some immune-deficient patients.

In vivo growth of Epstein-Barr virus transformed B cells with mutations in latent membrane protein 2 (LMP2)

“…CD38 is found only on pre-B cells and plasma cells, but not on activated B cells [1,50]. Also associated with the SCID tumors is a large production of human Ig [13,38] and a reduction in the expression of EBNA2 and LMP1 [40,42]. Thus, there is a shift to a more differentiated plasma cell when EBV infected lymphocytes are grown in, or isolated from, SCID mice relative to the same infected B lymphocytes grown in vitro.…”

Identification of IgH gene rearrangement and immunophenotype in an animal model of Epstein–Barr virus‐associated lymphomas

“…With the extension of culture time and the passage times increasing, the EBV‐transformed lymphoblastoid cell line (LCL) was observed to have an evolutionary trend from polyclonal to virtually monoclonal [Ryan et al, ]. Pisa et al [] induced the formation of B‐cell original oligoclonal tumors by infecting EBV‐negative PBLs intraperitoneally inoculated in SCID mice with EBV during 34–45 days. Picchio et al [] found that time and clonality of lymphomagenesis was not consistent while inoculum PBLs from donors had different incidences in SCID mice.…”

“…Although the mouse is an otherwise ideal animal model, it cannot be infected with EBV. In our previous study [Gan et al, , ; Tang et al, ] and those of other researchers [Mosier et al, ; Pisa et al, ], EBV‐associated humanized lymphomas were induced in hu‐PBL/SCID chimeric mice, which were generated by transplanting normal human peripheral blood lymphocytes (PBL) into severe combined immunodeficiency (SCID) mice. The establishment of EBV infection and a tumor model induced by EBV based on hu‐PBL/SCID chimeric mice has provided important tools for research on EBV‐associated neoplasms.…”

“…There are still different opinions on whether the EBV‐related lymphoma in the hu‐PBL/SCID chimeric mice was lymphocyte proliferation or a monoclonal or oligoclonal tumor [Picchio et al, ; Pisa et al, ]. In this study, we collected lymphocytes from the peripheral blood of healthy adult blood donors and constructed hu‐PBL/SCID chimeric mice.…”