Role of IL-6 in promoting growth of human EBV-induced B-cell tumors in severe combined immunodeficient mice.

To investigate the role of IL-6 as a growth factor in EBV-induced B lymphoproliferative disorders in immune-suppressed patients, we analyzed two B cell lines derived from two different patients for IL-6 production, expression of the p80 chain of the IL-6 receptor, and the effects on cell growth in vitro and in vivo of neutralizing mAbs specific for IL-6. One of the cell lines (LCL41) was shown to produce large amounts of IL-6 and to express IL-6 receptors. Its in vitro growth was weakly inhibited by the anti-IL-6 MAb. After inoculation into SCID mice, this cell line provoked human B cell tumors, the growth of which was controlled by the anti-IL-6 mAb. Indeed, four i.v. infusions of 0.1 mg at days 30 to 42 after i.p. inoculation of cells led to complete remission in most mice and long term survival in 40% of cases. In contrast, the other B cell line (LCL48) produced smaller amounts of IL-6; its growth was not inhibited in vitro by the anti-IL-6 Ab and was poorly blocked in vivo in SCID mice (40% of remissions and 20% of long-term survival). In addition, a clone derived in vivo in SCID mice from LCL48 was completely IL-6-independent. These results demonstrate that B cell tumors transformed in vivo by EBV in immune-suppressed patients are heterogeneous with respect to IL-6 requirements for proliferation. An antitumoral effect in some of them can be achieved by neutralizing the IL-6-dependent proliferative loop.