PREVENTION AND ANTIVIRAL TREATMENT FOR EBV LYMPHOMAGENESIS

EBV 淋巴生成的预防和抗病毒治疗

• 批准号: 8410979
• 负责人: JOSEPH S PAGANO
• 金额: $ 22.8万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8410979
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Adverse effects; Affect; Alternative Therapies; Animal Model; Animals; Antiviral Agents; B-Cell Lymphomas; B-Lymphocytes; Blinded; Body Weight decreased; Cell Transplants; Cells; Clinical Trials Design; Controlled Study; Cytomegalovirus; Development; Disease; Dose; Epstein-Barr Virus Infections; Gene Rearrangement; Generations; Genomics; Hematopoietic stem cells; Human; Human Herpesvirus 4; Immune response; Immune system; Individual; Infection; Lymphoid; Lymphoid Cell; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Lytic; Lytic Phase; MS4A1 gene; Malignant Neoplasms; Modeling; Mus; Natural Killer Cells; Organ Transplantation; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phenotype; Placebo Control; Placebos; Prevention; Signal Transduction; Stem cells; System; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissue Donors; Transplant Recipients; Transplantation; Variant; Viral; Viral Load result; Virus; acquired immunodeficiency; antitumor agent; arm; base; cohort; control trial; design; dosage; effective therapy; experience; inborn immunodeficiency; infected B cell; latent infection; maribavir; mouse model; pilot trial; placebo controlled study; prevent; prospective; reconstitution; rituximab; standard of care; transmission process; tumor

DESCRIPTION (provided by applicant): Fifty years after discovery of Epstein - Barr virus there is still no effective treatment to interrpt pathogenesis of any EBV infections including those that result in fatal B-cell lymphomas in patients with acquired or inborn immunodeficiency. Rapid development of humanized mice models engrafted with transplanted human hematopoietic stem cells that generate human B, T, and NK cells and a reconstituted human immune system have now provided small animal models suitable for treatment of studies human EBV disease. Infection of humanized NOD/SCID ?C-/- (NSG) mice with EBV produces infection that proceeds from a subclinical phase during which virus is replicated to development of polyclonal EBV B-cell lymphoproliferative disease and ultimately lethal CD20+, EBV EBER-positive, large-cell monoclonal B-cell lymphomas. In a single Aim we will infect with EBV cohorts of NSG mice reconstituted with stem cells from single donors for controlled trials designed to test whether an anti-EBV drug, Maribavir (MBV) alone or together with Rituximab can abort or retard progression from the reversible polyclonal lymphoproliferative phase of disease, when there is cell-to-cell transmission of virus, to irreversible monoclonal lymphoma. Polyclonal and monoclonal phases will be distinguished both by IgH gene rearrangements and EBV genomic terminal probe analyses. Basis for comparisons between treatment and placebo groups will be survival of animals analyzed with Kaplan-Meier survival curves and for statistical significance. These studies will be conducted in blinded fashion and will provide the first prospective, placebo-controlled trials of whether an antiviral drug, either alone or together with the nontoxic anti-tumor agent Rituximab, can affect the course of an EBV malignancy. Results may provide the basis for a nontoxic alternative therapy for these ultimately lethal post-transplant lymphomas. Results may also be of use in patients with AIDS who have rising EBV viral loads that may herald genesis of B-cell lymphomas. PUBLIC HEALTH RELEVANCE: Epstein-Barr virus infection causes B-cell lymphomas in patients who are immunodeficient because they have AIDS or are to receive a transplanted organ. EBV infection of new varieties of humanized mice that have a reconstituted human lymphoid system produces B-cell lymphomas identical to those in humans. These will be the first controlled studies to show whether an anti-EBV drug will prevent or slow genesis of these ultimately fatal lymphomas.

描述（由申请人提供）： 发现爱泼斯坦 - 巴尔病毒五十年后，仍然没有有效治疗任何EBV感染的发病机理，包括那些因获得或先天性免疫缺陷患者而导致致命B细胞淋巴瘤的感染。人性化小鼠模型的快速开发，这些模型被移植的人类造血干细胞产生人类B，T和NK细胞以及重建的人类免疫系统现在提供了适合治疗研究人EBV疾病的小动物模型。带有EBV的人源化点头/SCID的感染c - / - （NSG）小鼠会产生从亚临床阶段进行的感染，在此期间，病毒被复制到多克隆EBV B-cell淋巴细胞增生性疾病的发展，并最终致死CD20+EBV Eber eber-cell-cell monoclonal monoclonal b-Cell lymphom lymphom。在一个目的中，我们将与EBV同类的NSG小鼠同伴感染，与单个供体的干细胞重构，用于对照试验，旨在测试抗EBV药物，Maribavir（MBV）是否或与利妥昔单抗一起堕胎或与疾病的可逆性淋巴类药物传播的疾病传播相结合或降低。淋巴瘤。多克隆和单克隆阶段将通过IGH基因重排和EBV基因组末端探针分析来区分。治疗和安慰剂组之间比较的基础将是用Kaplan-Meier生存曲线分析的动物的存活，并且具有统计学意义。这些研究将以盲目的方式进行，并将提供第一个前瞻性，安慰剂控制的试验，即单独或与无毒的抗肿瘤剂利妥昔单抗一起使用抗病毒药是否会影响EBV恶性肿瘤的过程。结果可能为这些最终致命的移植后淋巴瘤的无毒替代疗法提供了基础。结果也可能用于艾滋病患者的EBV病毒载量增加，而EBV病毒负荷可能预示了B细胞淋巴瘤的发生。 公共卫生相关性： 爱泼斯坦 - 巴尔病毒感染引起免疫缺陷患者的B细胞淋巴瘤，因为他们患有艾滋病或接受移植器官。具有重建人类淋巴系统的人性化小鼠的EBV感染可产生与人类相同的B细胞淋巴瘤。这些将是首先证明抗EBV药物最终造成致命淋巴瘤的起源或减慢起源的对照研究。