LYMPHOCRYPTOVIRUS-ASSOCIATED PTLD VIRAL TRANSCRIPT EXPRESSION IN 8 XENOTRANSPLANTED CYNOMOLGUS MACAQUES

The aim of this work is to characterize posttransplant lymphoproliferative disorders (PTLD), frequently related to Epstein Barr Virus, observed in 8 adult immunosuppressed cynomolgus macaques, which received neural precursors from CTLA4Ig transgenic pigs to treat a pharmacologically-induced form of Parkinson's disease. The mean time of occurrence of the first clinical signs of PTLD was 177.62 days and the mean survival time was 199.87 days. 87.5% of PTLD occurred in the nasal cavity (50%), intestinal tract (50%), or both (12.5%); 50% with lymph nodal involvement. The histological diagnosis and immunohistochemical profile (anti-CD3, anti-CD5, anti-CD20, anti-CD79cyt, Ki-67) is compatible with a monomorphic PTLD, most frequently diffuse large B-cell lymphoma, high grade. Double-labeled immunohistochemistry for Epstein-Barr virus nuclear antigen (EBNA)-2 and CD20 revealed a high percentage of CD20+ neoplastic cells also positive for EBNA-2, while CD3+ cells in the tumors were negative for EBNA2. RT-PCR of transcripts EBNA-1 and Latent Membrane Protein-1 (LMP-1) have been performed in neoplastic cells from 5/8 PTLD primates and 2 hyperplastic lymph nodes from 2 PTLD+ primates (control). A consensus-PCR with specificity for EBNA-2 gene was performed on PTLD+ samples with a 92% of sequence identity between Rhesus and cynomolgus viruses. EBNA-1 and EBNA-2 expression was demonstrated in all PTLD+ specimens (no expression in controls). Four different RT-PCR assays failed to detect LMP-1 in all specimens. This report identifies in detail the pathological features of PTLD in cynomolgus monkeys in the setting of neuronal transplantation and a specific pattern of viral transcript expression (EBNA-1+ EBNA-2+ LMP-1-) in Lymphocryptovirus-associated PTLD.