Role of HERV-K18 Superantigen in EBV lymphomagenesis

HERV-K18 超抗原在 EBV 淋巴瘤发生中的作用

• 批准号: 6805607
• 负责人: NATALIE A SUTKOWSKI
• 金额: $ 7.02万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805607
• 关键词: B lymphocyte; Epstein Barr virus; Retroviridae; SCID mouse; T lymphocyte; antigen presenting cell; antiviral antibody; clinical research; genetically modified animals; human subject; leukocyte activation /transformation; lymphoma; oncogenic virus; superantigens; transfection; transfection /expression vector; viral carcinogenesis; virus antigen

DESCRIPTION (provided by applicant): More than 90% of adults are latently infected throughout their lifetime with the ubiquitous herpesvirus Epstein-Barr virus (EBV). While EBV infection is usually asymptomatic during childhood, it is estimated that half of first-time infected adolescents or adults develop infectious mononucleosis, a disease characterized by polyclonal B cell activation and massive expansion of T cells. EBV is an oncogenic virus; it is associated with Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinoma. At least 1% of organ and bone marrow transplant recipients develop EBV+ lymphomas; and EBV lymphoproliferative disorders are common in AIDS patients. The tumors are often associated with vast T cell infiltrates. The SCID/hu mouse is well accepted as an animal model for EBV lymphomagenesis, because SCID mice adoptively transferred with EBV seropositive PBMC from healthy human donors develop EBV+ B cell lymphomas at a high rate. These tumors are strictly T cell dependent and can be prevented by blocking the B-T interaction. We have recently established that EBV transactivates a human endogenous retrovirus, HERV-K18, that encodes a superantigen, which strongly activates T cells. This is the first described report of a pathogen inducing a host cell superantigen. We propose that HERV-K18 Env superantigen activated T cells contribute to EBV lymphomagenesis. This proposal seeks to test whether blocking the superantigen driven T cell response prevents tumorigenesis in the SCID/hu lymphoma mouse model. We propose to block T cell activation by: I. developing monoclonal antibodies specific for the HERV-K18 superantigen; II. blocking CD28/ICOS costimulation; III. induction of T cell anergy; and IV. ligation of immuno-inhibitory receptor PD-1. Since several other herpesviruses are associated with superantigen or superantigen-like activity, these experiments may have broad-reaching implications for herpesvirus biology. Overall, these studies represent a completely new approach towards understanding the potential role of T cells in herpesvirus oncogenesis.

描述（由申请人提供）：超过90％的成年人在一生中被无处不在的疱疹病毒Epstein-Barr病毒（EBV）受到潜在感染。 虽然EBV感染通常在儿童期无症状，但据估计，首次感染的青少年或成年人中有一半会发展出感染性单核细胞增多症，这种疾病以多克隆B细胞激活和T细胞的大量扩张为特征。 EBV是一种致癌病毒；它与伯基特的淋巴瘤，霍奇金病和鼻咽癌有关。 至少1％的器官和骨髓移植受者会出现EBV+淋巴瘤； EBV淋巴增生性疾病在艾滋病患者中很常见。 肿瘤通常与大量的T细胞浸润有关。 SCID/HU小鼠被很好地接受为EBV淋巴瘤发生的动物模型，因为SCID小鼠从健康的人类供体中采用EBV血清阳性PBMC传递，以高速率发展出EBV+ B细胞淋巴瘤。 这些肿瘤严格取决于T细胞，可以通过阻断B-T相互作用来预防。 我们最近确定EBV对人体内源性逆转录病毒herv-k18进行了反式激活，该逆转录病毒编码了超抗原，该超抗原强烈激活T细胞。 这是诱导宿主细胞超抗原的病原体的第一个描述的报告。 我们提出，HERV-K18 ENV超抗原激活的T细胞有助于EBV淋巴作用。 该建议旨在测试阻断超抗原驱动的T细胞反应是否可以防止SCID/HU淋巴瘤小鼠模型中的肿瘤发生。 我们建议通过以下方式阻止T细胞激活：I。开发针对HERV-K18超抗原的单克隆抗体； ii。阻止CD28/ICOS共刺激； iii。诱导T细胞消极；和IV。免疫抑制受体PD-1的连接。 由于其他几种疱疹病毒与超抗原或超抗原样活动有关，因此这些实验可能对疱疹病毒生物学具有广泛的影响。 总体而言，这些研究代表了一种全新的方法，用于了解T细胞在疱疹病毒肿瘤发生中的潜在作用。