Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man.

Abstract

Indeed, in vitro-transformed LCLs also grow when inoculated into SCID mice, the frequency of tumor outgrowth correlating with the in vitro growth phenotype ofthe LCL which is itself determined by the identity of the transforming virus (i.e., type 1 or type 2 EBV). Histologically the PB1.r derived hu-SCID tumors resemble the EBV + large cell lymphomas that develop in immunosuppressed patients and, like the human tumors, often present at multiple sites as individual monoclonal or oligoclonal foci. The remarkable efficiency oftumor development in the hu-SCID model suggests that lymphomagenesis involves direct outgrowth of EBVtransformed B cells without requirement for secondary genetic changes, and that selection on the basis of cell growth rate alone is sufficient to explain the monoclonal/oligoclonal nature of tumor foci. EBV + large cell lymphoma of the immunosuppressed may arise in a similar way. T he C.B-17 scid/scid mutant strain ofmouse (hereafter referred to as the SCID mouse) exhibits a severe combined immunodeficiency characterized by the absence of mature B and T lymphocytes (1) ; indeed, the mutation is thought to affect a component of the recombinase enzyme system involved in Ig and TCR gene rearrangements (2-4). The unexpected finding that mice carrying the SCID mutation could be grafted successfully with human (hu) haematopoietic cells has opened the way to the use ofthe hu-SCID chimeric mouse as a model for studying human immune-function in vivo (5-7). In addition, one of the original papers describing such engraftment showed that SCID mice reconstituted with high numbers of(hu-PBIJSCID mice) often developed lymphomas of B cell origin ifthe donor lymphocytes were from individuals with serological evidence of infection with EBV; these tumors were shown to carry EBV DNA but were otherwise poorly characterized (5) . It was immediately apparent from these studies that SCID mice could provide a potentially interesting in vivo model of human B lymphomagenesis involving an important viral pathogen .EBV is a human herpesvirus that in vitro has potent growth transforming activity for resting B lymphocytes but that in vivo is carried as an asymptomatic and persistent infection by >90% of adults worldwide . The virus is, however, consistently associated with two types of B cell malignancies: (a) large cell lymphomas which arise in immunocompromised individuals such as post-transplant patients (8, 9), and (b) the high incidence, or "endemic," form of Burkitt's lymphoma (BL)t which is geographically restricted to equatorial regions of Africa and Papua New Guinea where malaria is holoen-1 Abbreviations used in this paper. BL, Burkitt's lymphoma ; LCL, lymphoblastoid cell lines ; NGS, normal goat serum; NRS, normal rabbit serum ; VCA, viral capsid antigen complex .

Induction of Chromosomal Aberrations and Growth-Transformation of Lymphoblastoid Cell Lines by Inhibition of Reactive Oxygen Species-Induced Apoptosis with Interleukin-6

“…causes EBV-positive lymphoproliferative diseases with or without chromosomal aberrations (Glaser et al, 1993;Rowe et al, 1991). Therefore, we attempted to clarify whether IL-6 promotes the transformation of LCLs in vitro with or without induction of genetic damages.…”

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

“…It is unclear, though, how latently EBV-infected B cells escape elimination by T cells, in particular during the latency III program that is characterized by a considerable antigenic load and an activated state expected to increase the immunogenicity of B cells (23). In latency III, MHC I, MHC II, and T-cell-coactivating molecules are highly expressed (24,25), but nonetheless many epitopes are suboptimally recognized by CD8 + T cells (26,27). Therefore, it is likely that unknown immunoevasive mechanisms operate in these latently infected B cells.…”

Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells

“…EBV-transformed human B cells will cause fatal lymphoproliferative disease when transferred into a nonimmune environment such as a mouse with severe combined immunodeficiency (SCID) (Rowe et al, 1991), but only when T cells are also transferred (Veronese et al, 1992). Similarly, the load of MHV-68 infected B cells rises during splenomegaly, but is dependent on T cell help.…”