Low cell dosage of lymphoblastoid human cell lines EBV+ is associated to chronic hepatitis in a minority of inoculated nu/nu mice

It has been suggested that an atypical course of primary infection by EBV a nd the reactivation of EBV infection in transplanted patients may induce he patitis. We explored the possibility to dissect the infectious activity fro m the ability to promote B lymphocyte proliferation in vivo by injecting in nu/nu mice a low number (2 x 10(6) - 0.05 x 10(6)) of cells from CE a norm al human bone marrow-derived B cell line. This line carries an endogenous E BV in episomal and linear forms. Twenty nu/nu mice were inoculated subcutan eously with the B cell line CE and a matched group with the cell line RAG o btained by EBV in vitro infection of normal human peripheral blood. The mic e injected with the CE line did not develop a lymphoproliferative disease, but 5 of them displayed typical histopathological lesions of chronic hepati tis without involvement of other organs. Similar results were obtained in 2 out of 20 animals in the RAG group. A close association between liver lesi ons and a previous EBV infection, by putative circulating B lymphoblastoid cells releasing their EBV, was established by PCR and by in situ hybridizat ion with BamHI "W" DNA probe. This latter probe detected the presence of ab out 15% of positive cells only in affected livers. In addition, the rare de tection in some hepatocytes of "A" type Cowdry bodies would suggest the occ urrence of continuous EBV replication although at a very low level, These d ata show that we succeeded in dissecting the infectious from the proliferat ive activity of the endogenous EBV carrier CE cell line. This provides in a ddition a promising model for chronic EBV-associated hepatitis. (C) 2002 Wi ley-Liss, Inc.