PROCUREMENT OF TISSUE FOR MAKING EPSTEIN-BARR VIRUS (EBV) SPECIFIC CYTOTOXIC T

采购用于制备 Epstein-Barr 病毒 (EBV) 特异性细胞毒性 T 的组织

• 批准号: 8166709
• 负责人: HELEN E HESLOP
• 金额: $ 0.11万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166709
• 关键词: Animals; Antibodies; Antigens; B-Lymphocytes; Back; Blood; Body Fluids; Bone Marrow Transplantation; CD8B1 gene; Cells; Chronic; Companions; Computer Retrieval of Information on Scientific Projects Database; Cytotoxic T-Lymphocytes; Defense Mechanisms; Development; Donor person; EBV-Specific Cytotoxic T-Lymphocyte; EBV-associated disease; Epithelial Cells; Epstein-Barr Virus Infections; Fatigue; Fever; Funding; Future; Genome; Grant; Growth; Hepatosplenomegaly; Herpesviridae; Hodgkin Disease; Human; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunologic Monitoring; In Vitro; Individual; Infection; Infectious Mononucleosis; Institution; LMP1; Life; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Mediating; Membrane Proteins; Nasopharynx Carcinoma; Nuclear Antigens; Organ Transplantation; Oropharyngeal; Patients; Peptide Fragments; Population; Proteins; Protocols documentation; Research; Research Personnel; Resources; Risk; Saliva; Serum; Solid; Source; Surface; Syndrome; System; T-Lymphocyte; Tissue Procurements; Tissues; United States National Institutes of Health; Viral Antigens; Virus; acquired immunodeficiency; cancer cell; cytotoxic; immunosuppressed; infected B cell; lytic replication; prevent; research study; response; transmission process

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a procurement only protocol This is a companion protocol to the following GCRC supported research studies: H-9935, 6676, 9454, 8216 Using blood obtained from eligible subjects, will enable the ability to produce EBV specific cytotoxic T lymphocytes (CTLs). The objective of this protocol is to obtain tissue (blood) for the purpose of making EBV specific cytotoxic T lymphocytes (CTLs). If successful, these cells may be given back to the patient in the future should they become eligible for one of the EBV-CTL research studies being conducted. Epstein-Barr virus (EBV) is a human lymphotropic herpes virus able to infect and immortalize human B lymphocytes. In the primary infection, occurring via saliva exchange, EBV infects oropharyngeal epithelial cells that support the lytic replication and allow the transmission of the virus to circulating B cells. Once in the B cells, the EBV genome is maintained in a latent form. B cells infected with EBV in vitro undergo transformation as result of the expression of latency-associated transforming proteins. These B cells always express a number of EBV gene products including the nuclear antigens EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA 3C, EBNA LP and the latent membrane proteins LMP1 and LMP2. The proliferation of EBV-infected cells expressing these latency-associated transforming proteins is controlled by specific T cells. Hence, in a majority of the population, primary infection is asymptomatic or results in a mild and self-limiting illness (infectious mononucleosis, IM). Following infection, individuals are life-long virus carriers. Unlike patients with a normal immune system, people with congenital or acquired immunodeficiency are highly susceptible to the development of EBV driven lymphoproliferative disease (EBV-LPD) since the reactivation of EBV is less tightly controlled by a cell-mediated response. Evidence suggests that EBV specific CD8+ CTLs are the most important defense mechanism against outgrowth of EBV infected B cells. These cells recognize peptide fragments derived from viral antigens expressed in association with MHC molecules on the surface of B cells. The state of reduced or suppressed T cell activity in immunosuppressed individuals interferes with the immunosurveillance system and increases the risk of EBV-driven proliferation of the infected cells, allowing Bcell clones with a growth advantage to emerge and result in one or more clonal populations. Another syndrome associated with defective immune control of EBV is severe chronic active EBV (SCAEBV) infection syndrome where patients present with chronic fatigue, fever, hepatosplenomegaly and lymphoadenopathy . Patients characteristically have elevated antibody titers to the viruscapsid antigen and low or absent antibody to EBNA and free virus in serum or other body fluids. EBV is also associated with other malignancies and is found in the malignant cells of 40% of patients with Hodgkin Disease, and most cases of nasopharyngeal carcinoma. Studies in animals and humans have shown that EBV specific T-cells can be generated ex-vivo to produce an anti- EBV infected cell immune response. We have used this approach in patients post bone marrow transplant where donor derived EBV-specific CTLs have been effective both in preventing and treating EBV lymphoproliferation. We are now extending this approach to other EBV-associated diseases including EBV lymphomas arising after solid organ transplant, EBV positive Hodgkin disease, nasopharyngeal carcinoma and severe chronic EBV infection.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这是仅限采购的协议 这是以下 GCRC 支持的研究的配套协议： H-9935、6676、9454、8216 使用从合格受试者获得的血液，将能够产生 EBV 特异性细胞毒性 T 淋巴细胞 (CTL)。 该协议的目的是获取组织（血液），以制造 EBV 特异性细胞毒性 T 淋巴细胞 (CTL)。如果成功的话，如果这些细胞有资格参加一项正在进行的 EBV-CTL 研究，将来可能会将这些细胞返还给患者。 EB 病毒 (EBV) 是一种嗜淋巴细胞疱疹病毒，能够感染人类 B 淋巴细胞并使其永生化。在通过唾液交换发生的初次感染中，EBV 感染支持裂解性复制并允许病毒传播至循环 B 细胞的口咽上皮细胞。一旦进入 B 细胞，EBV 基因组就会保持潜伏状态。体外感染EBV的B细胞 转化是潜伏期相关转化蛋白表达的结果。这些B细胞总是表达许多EBV基因产物，包括核抗原EBNA1、EBNA2、EBNA3A、EBNA3B、EBNA 3C、EBNA LP和潜伏膜蛋白LMP1和LMP2。表达这些潜伏期相关转化蛋白的 EBV 感染细胞的增殖受到特定 T 细胞的控制。因此，在大多数人群中，原发感染是无症状的或导致轻微的自限性疾病（传染性单核细胞增多症，IM）。感染后，个体成为终生病毒携带者。与免疫系统正常的患者不同，先天性或后天性免疫缺陷患者极易发生 EBV 驱动的淋巴增殖性疾病 (EBV-LPD)，因为 EBV 的再激活不受细胞介导反应的严格控制。有证据表明，EBV 特异性 CD8+ CTL 是针对 EBV 感染的 B 细胞生长的最重要的防御机制。这些细胞识别源自与 B 细胞表面 MHC 分子相关的病毒抗原的肽片段。免疫抑制个体中 T 细胞活性降低或抑制的状态会干扰免疫监视系统，并增加 EBV 驱动的受感染细胞增殖的风险，从而使具有生长优势的 B 细胞克隆出现并产生一个或多个克隆群体。另一种与 EBV 免疫控制缺陷相关的综合征是严重慢性活动性 EBV (SCAEBV) 感染综合征，患者出现慢性疲劳、发热、肝脾肿大和淋巴结病。患者的特征是病毒衣壳抗原抗体滴度升高，EBNA 抗体滴度低或不存在，血清或其他体液中存在游离病毒。 EBV 还与其他恶性肿瘤相关，在 40% 霍奇金病患者和大多数鼻咽癌患者的恶性细胞中发现。对动物和人类的研究表明，EBV 特异性 T 细胞可以在体外产生，以产生抗 EBV 感染的细胞免疫反应。我们已在骨髓移植后的患者中使用了这种方法，其中供体来源的 EBV 特异性 CTL 在预防和治疗 EBV 淋巴增殖方面均有效。我们现在将这种方法扩展到其他 EBV 相关疾病，包括实体器官移植后出现的 EBV 淋巴瘤、EBV 阳性霍奇金病、鼻咽癌和严重慢性 EBV 感染。