ROLE OF GROWTH FACTORS IN EBV-POSITIVE POST-TRANSPLANT L

生长因子在 EBV 阳性移植后 L 中的作用

• 批准号: 6161313
• 负责人: G TOSATO
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161313
• 关键词: B lymphocyte; Epstein Barr virus; autocrine; cell line; gel filtration chromatography; growth factor; immunoaffinity chromatography; interleukin 6; ion exchange chromatography; lactates; leukocyte activation disorder; protein purification; recombinant proteins; transplantation immunology

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.

涉及自然感染EB病毒（EBV）的B细胞的恶性增殖性疾病是消融治疗的毁灭性并发症。 该项目旨在阐明生长因子对EBV阳性淋巴组织增生性疾病发展的贡献。 EB病毒（EBV）引起的B细胞永生化和EBV感染的B细胞在体外的持续生长依赖于B细胞分泌培养上清液中的生长因子和病毒感染的B细胞对这些因子的利用。 实验室的主要兴趣是鉴定负责EBV永生化细胞中自分泌生长因子活性的化合物及其在B细胞永生化/转化中的作用。 最初，我们确定白细胞介素-6（IL-6）是由EBV永生化B细胞产生的自分泌生长因子之一。 随后，我们确定乳酸是另一种由EBV永生化B细胞产生的更丰富和更有效的自分泌生长因子。 最近，我们集中研究了PEL（原发性渗出性淋巴瘤，常合并EBV和KSHV感染）对生长因子的需求。这些淋巴瘤发生在免疫抑制的艾滋病患者中，预后非常差。使用来自PEL的永生化细胞系，我们已经确定了人IL-10和病毒IL-6，但不是人IL-6，作为这些细胞系的自分泌生长因子。因此，针对人IL-10和病毒IL-6的中和抗体显著抑制PEL细胞的自发增殖。我们在NIH 3 T3中表达了病毒IL-6，并将这些细胞接种到无胸腺小鼠体内。使用这个实验系统，我们已经确定了病毒IL-6的其他生物学特性。 这种细胞因子促进骨髓、红细胞和巨核细胞谱系中的造血;脾和淋巴结中的浆细胞增多;肝脾肿大;多克隆高丙种球蛋白血症;以及VEGF产生增加。 针对鼠VEGF的中和抗体防止了腹膜内接种PEL的免疫抑制小鼠中的PEL发展。提示病毒性IL-6和VEGF在PEL发病中起重要作用。