Human B-cell lymphoma in severe combined immunodeficient mice after active infection with Epstein-Barr virus.
BACKGROUND: B-cell lymphomas (BCL) occur with increased frequency in immunosuppressed patients. BCL develop in severe combined immunodeficient (SCID) mice after engraftment with human peripheral blood leukocytes (PBL; hu-PBL-SCID mice) and infection with Epstein-Barr virus (EBV). The contributions of latent and active EBV infection to BCL development, the potential enhancing effects of immunosuppressive therapy, and inhibitory effects of antiviral therapy on the development of BCL in this model were studied. METHODS: SCID mice were engrafted with PBL from EBV-seropositive donors (latent infection), PBL from EBV-seronegative donors followed by infection with EBV (active infection), PBL from EBV-seropositive donors followed by infection with EBV (latent plus active infection), or EBV-transformed B-lymphoblastoid cells and monitored for the development of BCL. Hu-PBL-SCID mice were treated with the immunosuppressive agents cyclosporine or methylprednisolone or the antiviral agents acyclovir or ganciclovir. RESULTS: Tumors developing in hu-PBL-SCID mice were high-grade lymphomas of human B-cell origin and contained EBV-DNA. BCL developed in 70% of mice 11 to 14 weeks after latent infection. BCL developed after 4 to 7 weeks in all hu-PBL-SCID mice after active infection. Treatment with cyclosporine or methylprednisolone had no effect on BCL development after active infection, but inhibited rather than enhanced the development of BCL in latently infected mice. Ganciclovir, but not acyclovir, inhibited BCL development after active infection. CONCLUSIONS: The hu-PBL-SCID mouse provides an in vivo model of BCL associated with immunosuppression. Active EBV infection results in the rapid development of BCL in this model even when latently infected B cells are present. Inhibition of BCL development in latently infected hu-PBL-SCID mice by immunosuppressive therapy may reflect inhibition of a T-cell/B-cell interaction necessary for B-cell activation. Inhibition of BCL development by granciclovir suggests a possible role for this agent in the management of BCL associated with immunosuppression.
Boyle, TJ; Tamburini, M; Berend, KR; Kizilbash, AM; Borowitz, MJ; Lyerly, HK
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