The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders

Whereas the standard immunosuppressive agents foster development of posttra nsplant lymphoproliferative disorders (PTLDs), the impact of RAD, a macroli de with potent immunosuppressive properties, and other immunosuppressive ma crolides on these disorders remains undetermined. We found that RAD had a p rofound inhibitory effect on in vitro growth of six different PTLD-like Eps tein-Barr virus+ lymphoblastoid B cell lines. Similar to normal Tcells, RAD blocked cell-cycle progression in PTLD-like B cells in the early (G(0)/G(1 )) phase. Furthermore, RAD increased the apoptotic rate in such cells. The drug also had a profound inhibitory effect on the growth of PTLD-like Epste in-Barr virus+ B cells xenotransplanted s.c. into SCID mice. The degree of the RAD effect varied among the three B cell lines tested and was proportio nal to its effects on the cell lines in vitro. In this in vivo xenotranspla nt model, RAD markedly delayed growth or induced regression of the establis hed tumors. In one line, it was able to eradicate the tumor in four of eigh t mice. When RAD treatment was initiated before tumor cell injection, a mar ked inhibition of tumor growth was seen in all three lines. In two of them, the drug prevented tumor establishment in approximately 50% of mice (5/11 and 5/8). In summary, RAD is a potent inhibitor of PTLD-like cells in vitro and in vivo. These findings indicate that, in contrast to the standard imm unosuppressive agents, macrolides such as RAD may be effective in preventio n and treatment of PTLDs.