Lymphoproliferative diseases involving B cells naturally infected with Epstein-Barr virus (EBV) are devastating complications of ablative therapies. This project aims to clarify the contribution of growth factors to the development of EBV-positive lymphoproliferative diseases. B cell immortalization by Epstein-Barr virus (EBV) and the continuous growth of B cells infected with EBV in vitro is dependent upon B cell secretion of growth factors in the culture supernatant and utilization of these factors by B cells infected with the virus. A major interest of the laboratory has been the identification of the compounds responsible for autocrine growth factor activity in EBV-immortalized cells and their role in B-cell immortalization/ transformation. Initially, we identified Interleukin-6 (IL-6) as one of the autocrine growth factors produced by EBV-immortalized B cells. Subsequently, we identified lactic acid as being another, more abundant and more potent autocrine growth factor produced by EBV-immortalized B cells. More recently, we have focused on growth factor requirements of PEL, primary effusion lymphomas which are often coinfected with EBV and KSHV. These lymphomas arise in immunosuppressed individuals with AIDS and have a very poor prognosis. Using immortalized cell lines derived from PEL, we have identified human IL-10 and viral IL-6, but not human IL-6, as autocrine growth factors for these cell lines. Thus, neutralizing antibodies against human IL-10 and viral IL-6 profoundly inhibit the spontaneous proliferation of PEL cells. We have expressed viral IL-6 in NIH3T3 and inoculated these cells into athymic mice. Using this experimental system, we have identified other biological properties of viral IL-6. This cytokine promotes hematopoiesis in the myeloid, erythroid, and megakaryocytic lineages; plasmacytosis in spleen and lymph nodes; hepatosplenomegaly; polyclonal hypergammaglobulinemia; and increased production of VEGF. Neutralizing antibodies against murine VEGF prevented PEL development in immunosuppressed mice inoculated intraperitoneally with PEL. This suggests that viral IL-6 and VEGF play an important role in PEL pathogenesis.
