ANIMAL MODEL FOR HUMAN EB VIRUS-RELATED TUMOR: PATHOGENESIS OF RABBIT LYMPHOMA INDUCED BY SIMIAN EBV-RELATED VIRUS

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Animal models of human EBV-associated diseases are essential to elucidate the pathogenesis of EBV-infection and EBV-associated diseases. Here we reported our two newly developed rabbit models of lymphoproliferative diseases (LPD) induced by simian EBV-like viruses. The first is Cynomolgus-EBV-induced T-cell lymphomas in rabbits inoculated intravenously (77-90%) and orally (82- 89%) about 2 -5 months later. EBV-DNA was detected in peripheral blood by PCR since 2 days after oral inoculation while anti-EBV-VCA IgG was raised 3 weeks later. Rabbit lymphomas and their cell lines contained EBV-DNA and expressed EBV-encoded RNA-1 (EBER-1). Rabbit lymphomas and their cell lines contained EBV-DNA and expressed EBV-encoded RNA-1 (EBER-1). Rabbit lymphoma cell lines, some of which have specific chromosomal abnormality, showed tumorigenicity in nude mice. The second is the first and unique animal model for EBV-infected T-cell LPD with virus-associated hemophagocytic syndrome (VAHS) using rabbits infected with the baboon EBV-like herpesvirus, Herpesvirus papio (HVP). Rabbits inoculated intravenously with HVP-producing cells showed increased anti-EBV-VCA-IgG titers, and most (85%) subsequently died of fatal LPD and VAHS, with bleeding and hepatosplenomegaly, within a relatively short time (22-105 days). Peroral spray of cell-free HVP induced viral infection with seroconversion in 3 out of 5 rabbits, with 2 of the 3 infected rabbits dying of LPD with VAHS. Atypical T lymphocytes containing HVP-DNA and expressing EBER-1 were observed in many organs. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. These rabbit models are also useful and inexpensive alternative experimental model systems for studying the biology and pathogenesis of EBV, and prophylactic and therapeutic regimens, especially in relation to human fatal EBV-related LPD and VAHS.