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

EB病毒（EBV），嗜异性阳性的病原体 急性传染性单核细胞增多症，是一种成功的病原体， 无症状的大多数正常成年个体。 尽管他们 无限生长的潜力，B细胞仅天然感染EBV 很少引起淋巴增生性疾病的人。信贷等 成功抑制主要归因于T细胞免疫。 严重的T细胞免疫缺陷，如发生在艾滋病和固体 器官移植受者，可能导致不受控制的扩张， 自然感染EB病毒的B淋巴细胞与EB病毒的发生 淋巴组织增生性疾病 高达32%的实体器官移植 接受者可能发展淋巴增生性疾病， EBV感染的B细胞。 IL-6是一种多功能细胞因子，由 单核细胞、成纤维细胞、内皮细胞和其他细胞类型促进 EBV感染的B细胞的生长，作为自分泌和/或旁分泌 生长因子 此外，我们和其他人发现，这种细胞因子 增加无胸腺小鼠中EB病毒永生化B细胞的致瘤性。 我们还发现血清/血浆IL-6生物活性异常升高， 尽管是短暂的，但在18例实体器官移植受者中， 移植后淋巴组织增生性疾病（PTLD）。 相比之下，只有 10例实体器官移植受者中有3例病程不复杂 移植后血清/血浆IL-6活性异常升高（P = 0.0007）。 最近，我们发现PTLD来源的内皮细胞 病变在体外自发分泌高水平的IL-6， 这表明内皮细胞可能是一个重要的来源， IL-6在PTLD患者中的作用 我们研究了持续的 内皮细胞产生IL-6，并确定EBV可感染 体外培养内皮细胞。 在与致死的 照射的EBV阳性但不是EBV阴性细胞系， 人脐带内皮细胞原位表达 EBV编码的EBER RNA。 内皮细胞感染EB病毒， 与显著的IL-6产生相关， 培养120天 这些研究将内皮细胞确定为靶点 EB病毒感染，并提出这种感染可能是 在PTLD的发病机制中起重要作用，并且可能与EBV的生命周期有关。 琼斯K，里维拉C，Sgadari C.，富兰克林J.，麦克斯·E Bhatia K.和 土里 Epstein-Barr病毒感染人内皮细胞 J. Exp. 182：255-262，1995中。

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.