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

嗜异性者的病原体--爱泼斯坦-巴尔病毒 急性传染性单核细胞增多症，是一种成功的人类病原体。 无症状地感染大多数正常的成年个体。在……里面 尽管B细胞具有无限生长的潜力，但它们自然感染了 EB病毒感染很少引起男性淋巴增生性疾病。 这种成功的节制应主要归功于T细胞 豁免权。严重的T细胞免疫缺陷，如艾滋病 和固体器官移植的接受者，会导致失控 自然感染EB病毒的B淋巴细胞的扩增和 淋巴增生性疾病的发展。高达32%的固体 器官移植受者可能患上淋巴增生性疾病 通常涉及EBV感染的B细胞。多功能白介素6 单核细胞、成纤维细胞、内皮细胞等产生的细胞因子 细胞类型促进EBV感染的B细胞的生长，起到 自分泌和/或旁分泌生长因子。此外，这种细胞因子还具有 已被证明可增加EBV永生化B细胞的致瘤性 无性系小鼠。此外，血清/血浆IL-6生物活性也被发现 18个实体器官中有17个异常升高，尽管是一过性的 移植受者，患有移植后淋巴增生性疾病 (PTLD)，平均最高水平为196.7 U/ml。这代表16.4 高于正常均值(11.3U/ml)。相比之下，只有十分之三的人 病程不复杂的实体器官移植受者 移植后血清/血浆IL-6活性异常升高 平均最大值为41.4U/ml，P=0.0007。当转移到单人时 细胞培养中，11例PTLD组织产生640~1.25106个IL-6U/ml 培养上清，平均最高水平为35,025个IL-6U/ml。 细胞分离实验表明，贴壁细胞， 被鉴定为非B细胞，是产生IL-6的主要来源 用PTLD组织进行体外培养。最近，我们试图鉴定这些细胞 负责PTLD组织中高水平的IL-6产生。我们的 初步实验表明，内皮细胞是 IL-6的细胞来源。我们尽可能地检查了几个机械装置 诱导内皮细胞产生IL-6。正在进行的实验已经 提示EBV对内皮细胞的感染可能是其原因 用于内皮细胞产生IL-6。因此，IL-6在高血压患者体内升高。 发生PTLD和EB病毒感染的移植后受者的循环 淋巴增生性病变内受感染的内皮细胞是 可能是IL-6的来源。

Epstein-Barr virus (EBV) the causative agent of heterophile-positive acute infectious monocleosis, is a successful pathogen in the human species, asymptomatically infecting 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, this cytokine has been shown to increase the tumorigenicity of EBV-immortalized B cells in athymic mice. Also, serum/plasma IL-6 bioactivity was found to be abnormally elevated, albeit transiently, in 17 of 18 solid organ transplant recipients, with post-transplant lymphoproliferative disease (PTLD), with a mean maximal level of 196.7 U/ml. This represents a 16.4 increase above the normal mean (11.3 U/ml). In contrast, only 3 of 10 solid organ transplant recipients with uncomplicated courses posttransplant had abnormally elevated serum/plasma IL-6 bioactivity (mean maximal level 41.4 U/ml, P = 0.0007). When transferred to single cell culture, the 11 PTLD tissues produced 640 to 1.25106 IL-6 U/ml in the culture supernatant, with a mean maximal level of 35,025 IL-6 U/ml. Cell separation experiments demonstrated that the adherent cells, identified as non-B cells, were the principal source of IL-6 production in vitro by PTLD tissue. Recently, we sought to identify the cells responsible for high-level IL-6 production in PTLD tissues. Our preliminary experiments demonstrated that the endothelial cells are the cellular source of IL-6. We examined several mechanims as possibly inducing IL-6 production by endothelial cells. Ongoing experiments have indicated that EBV infection of endothelial cells is the likely reason for endothelial cell production of IL-6. Thus, IL-6 is elevated in the circulation of post transplant recipients who develop PTLD and the EBV- infected endothelial cells within the lymphoproliferative lesions are the likely source of IL-6.