A ROLE FOR INTERLEUKIN-6 IN POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE

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Epstein-Barr virus (EBV), the causative agent of heterophile-positive acute infectious mononucleosis, is a successful pathogen that infects asymptomatically most normal adult individuals. In spite of their potential for unlimited growth, B cells naturally infected with EBV only rarely give rise to lymphoproliferative disease in man. Credit for such successful restraint is attributable, primarily to T cell immunity. Severe T cell immunodeficiency, such as that occurring in AIDS and solid organ transplant recipients, can result in the uncontrolled expansion of B lymphocytes naturally infected with EBV and the development of lymphoproliferative disease. As many as 32% of solid organ transplant recipients may develop lymphoproliferative disease generally involving EBV-infected B cells. IL-6, a multifunctional cytokine produced by monocytes, fibroblasts, endothelial cells, and other cell types promotes growth of EBV-infected B cells, acting as an autocrine and/or paracrine growth factor. In addition, we and others found that this cytokine increases the tumorigenicity of EBV-immortalized B cells in athymic mice. We also found that serum/plasma IL-6 bioactivity was abnormally elevated, albeit transiently, in 17 of 18 solid organ transplant recipients with post-transplant lymphoproliferative disease (PTLD). In contrast, only 3 of 10 solid organ transplant recipients with uncomplicated courses posttransplant had abnormally elevated serum/plasma IL-6 bioactivity (P = 0.0007). Recently, we found that endothelial cells derived from PTLD lesions spontaneously secrete high levels of IL-6 in vitro for up to four months, suggesting that endothelial cells might be an important source of IL-6 in PTLD patients. We examined possible mechanisms for sustained IL-6 production by endothelial cells, and determined that EBV can infect endothelial cells in vitro. After 3 to 4 weeks incubation with lethally irradiated EBV-positive but not EBV-negative cell lines, a proportion of human umbilical cord derived endothelial cells expressed in situ the EBV-encoded EBER RNAs. Endothelial cell infection with EBV was associated with significant IL-6 production that was sustained for up to 120 days in culture. These studies identify endothelial cells as targets for EBV infection and raise the possibility that this infection might be important in the pathogenesis of PTLD, and perhaps the life cycle of EBV. Jones K, Rivera C., Sgadari C., Franklin J., Max E., Bhatia K., and Tosato. Infection of Human Endothelial cells with Epstein-Barr virus. J. Exp. Med. 182: 255-262, 1995.