Malignant lymphoma induction in rabbits by intravenous inoculation of Epstein‐Barr‐virus‐related herpesvirus from HTLV‐II‐transformed cynomolgus leukocyte cell line (Si‐IIA)

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Abstract
Maignant lymphomas, which were usually of T‐cell type, were Induced in 10 of 13 (77%) male rabbits (Japanese white, 8/10; New Zealand white, 2/3) inoculated i.v. with HTLV‐II‐transformed simian (Cynomolgus) leukocyte cell line (Si‐IIA) cells. Of 7 rabbits injected with cell‐free pellets from Si‐IIA cultures, 5 also developed malignant lymphoma (15–28 days). Lymphoma development was completely inhibited by inactivation of cell‐free pellets from Si‐IIA culture with ethyl ether and was almost suppressed by neutralization of the cell‐free pellets with anti‐Si‐IIA sera. Herpesvirus particles were discovered very rarely in Si‐IIA cells, in addition to C‐type virus particles, by electron microscopy. Si‐IIA cells were positive for Epstein‐Barr‐virus(EBV)‐associated nuclear antigen (EBNA) by immunofluo‐resconce (IF) test. Antibody response to viral capsid antigen of EBV was also detected in sera from rabbits inoculated with Si‐IIA. EBV‐encoded RNA‐I (EBER‐I) was demonstrated in Si‐IIA, the tumor tissues and all rabbit tumor cell lines by in situ hybridization. EBV DNA was also detected in Si‐IIA and rabbit lymphoma cell lines by polymerase chain reaction (PCR) and Southern blotting. However, EBV DNA was amplified only by some primers complementary to human EBV sequence (B95–8), but not by other primers. Integration of HTLV‐II provirus genome could not be detected in Si‐IIA‐induced rabbit tumor cells. Moreover, no lymphoma was induced by inoculation of HTLV‐IIC and MOT (other HTLV‐II‐producing human cell lines), B95‐8 (EBV‐producing cell line) or TALL‐1 and peripheral leukocytes from normal Cynomolgus (controls). Neither Herpesvirus saimiri nor H. ateles (simian oncogenic viruses) were detected in Si‐IIA cells by IF test. These data suggest that the high rate of lymphoma induction in rabbits may not be caused by HTLV‐II, human EBV (B95–8) or well‐known simian oncogenic viruses, but by EBV‐related herpesvirus derived from Si‐IIA cells or HTLV‐IIA cells, with which Si‐IIA was established. The availability of this animal model promises to clarify the role of EBV in human lymphoma and provides a means of studying prophylactic and therapeutic regimens. © 1995 Wiley‐Liss, Inc.

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