Cellular Mechanisms of PTLD in Transplant Recipients

移植受者 PTLD 的细胞机制

• 批准号: 7808609
• 负责人: Olivia M Martinez
• 金额: $ 4.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-25 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808609
• 关键词: Adoptive Immunotherapy; Aftercare; Antibodies; Apoptosis; Attenuated; B-Cell Lymphomas; B-Cell Neoplasm; B-Lymphocytes; Benign; Biological Assay; Bone Marrow Transplantation; Cell Line; Cellular Immunity; Cessation of life; Child; Complex; Complication; Data; Development; Disease; EBV-associated malignancy; Goals; Growth; Growth Factor; Growth and Development function; Homologous Gene; Human; Human Herpesvirus 4; Hyperplasia; Immunity; In Vitro; Induction of Apoptosis; Interleukin-10; Lead; Life; Lymphoma; Lymphoproliferative Disorders; Malignant - descriptor; Mediating; Membrane Proteins; Mitogen-Activated Protein Kinase 3; Modeling; Molecular; Morbidity - disease rate; Natural Killer Cells; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Play; Prevention; Production; Protein Tyrosine Kinase; Proteins; Receptors, Antigen, B-Cell; Recruitment Activity; Reporting; Resistance; Role; Signal Transduction; Signal Transduction Pathway; Sirolimus; Solid; Testing; Therapeutic; Therapeutic Agents; Transplant Recipients; Transplantation; Tumor Cell Line; Tumor Necrosis Factor Ligand Superfamily Member 6; Viral; Viral Proteins; Work; autocrine; caspase-8; cell transformation; death receptor-4; human MAPK14 protein; human SYK protein; human TNFRSF10A protein; in vivo; infected B cell; inhibitor/antagonist; mTOR protein; mortality; neoplastic cell; novel; novel diagnostics; novel strategies; novel therapeutics; public health relevance; receptor; rituximab; small molecule; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Post-transplant lymphoproliferative disease (PTLD) describes a morphologically heterogeneous complication of solid organ and bone marrow transplantation that ranges from benign B cell hyperplasia to malignant lymphoma. The hallmark of PTLD is the development of Epstein Barr Virus (EBV)-associated B cell lymphomas. Currently, there are no established therapies for PTLD and reported mortality rates commonly exceed 50%. Multiple strategies have been utilized to treat patients with PTLD such as anti-viral drugs, B cell specific antibodies including anti-CD20 (Rituximab) and adoptive cellular immunotherapy. However, each of these approaches has distinct limitations. Our broad, long term objective has been to determine the cellular and viral proteins that are essential to the growth and survival of PTLD-associated EBV+ B cell lymphomas with the intent to identify novel candidates for therapeutic targeting. We hypothesize that EBV co-opts host cellular pathways to promote growth and survival of B cell tumors. In support of this hypothesis, we have defined a novel pathway by which the latent cycle EBV protein, latent membrane protein 1 (LMP1) induces production of human IL-10 (hIL-10) in infected B cells. hIL-10 acts as a potent autocrine growth factor in a variety of EBV+- associated malignancies including PTLD. We have also determined that the spleen tyrosine kinase (Syk), activated by the viral protein latent membrane protein 2A (LMP2A), is critical to the survival of PTLD- associated B cell lines. Moreover, our preliminary data indicate that a small molecule inhibitor of Syk significantly inhibits the growth and survival of PTLD-derived cell lines. Finally we demonstrate that LMP1 subverts host immunity through an NF:B-dependent pathway by conferring resistance to key death-receptor (DR) effector mechanisms utilized by CTL and NK cell to eliminate virally-infected and transformed cells. Our findings implicate the cellular protein, cFLIP in the resistance to DR-induced apoptosis. In this proposal we will target identified signal transduction pathways, and cellular proteins, induced by the key viral proteins LMP1 and LMP2a with the goal of inhibiting growth of PTLD-associated B cell lymphomas. To achieve these objectives we propose three specific aims. Specific Aim 1 will investigate the requirement for Syk in survival of PTLD-associated EBV+ B cell lymphomas and test, in a NOD/SCID model, the value of targeting Syk as a potential therapeutic strategy. Specific Aim 2 will define the LMP1-mediated activation of the PI3K/AKT signaling axis and its role in hIL-10 induction. Further, strategies to intervene in this pathway will be tested as a means to inhibit tumor growth in vivo. In Specific Aim 3, we will target the LMP1-induced cellular protein, cFLIP with the intent to boost the ability of host CTL to eliminate EBV-infected B cell lymphomas. We anticipate that these approaches will reveal novel, and effective, therapeutic options for the treatment of PTLD.7. PUBLIC HEALTH RELEVANCE: The development of Epstein Barr Virus-associated B cell lymphomas remains a serious, and often fatal, complication of solid organ and bone marrow transplantation. Currently, there are no established therapies for treatment of this disease. Thus, studies that identify and define novel targets for inhibiting tumor growth could lead to new diagnostic and therapeutic agents for prevention of this devastating disease.

描述（由申请人提供）：移植后淋巴增生性疾病（PTLD）描述了固体器官和骨髓移植的形态异质并发症，范围从良性B细胞增生到恶性淋巴瘤。 PTLD的标志是爱泼斯坦Barr病毒（EBV）相关的B细胞淋巴瘤的发展。目前，尚无针对PTLD的已建立疗法，报告的死亡率通常超过50％。多种策略已被用于治疗患有PTLD的患者，例如抗病毒药物，B细胞特异性抗体，包括抗CD20（利妥昔单抗）和收养细胞免疫疗法。但是，这些方法中的每一种都有不同的局限性。我们广泛的长期目标是确定对PTLD相关的EBV+ B细胞淋巴瘤的生长和存活至关重要的细胞和病毒蛋白，目的是识别用于治疗靶向的新候选者。我们假设EBV Co-OPTS宿主细胞途径促进B细胞肿瘤的生长和存活。为了支持这一假设，我们定义了一种新的途径，潜在循环EBV蛋白潜在膜蛋白1（LMP1）诱导了受感染的B细胞中人IL-10（HIL-10）的产生。 HIL-10在包括PTLD在内的各种EBV+相关的恶性肿瘤中充当有效的自分泌生长因子。我们还确定，由病毒蛋白潜在膜蛋白2a（LMP2A）激活的脾酪氨酸激酶（SYK）对于PTLD-相关B细胞系的存活至关重要。此外，我们的初步数据表明，SYK的小分子抑制剂显着抑制了PTLD衍生的细胞系的生长和存活。最后，我们证明了LMP1通过赋予CTL和NK细胞使用的钥匙死亡受体（DR）效应器机制来通过NF：B依赖性途径来颠覆宿主免疫，以消除病毒感染和转化的细胞。我们的发现暗示了细胞蛋白，CFLIP在对DR诱导的凋亡的抗性中。在此提案中，我们将靶向由关键病毒蛋白LMP1和LMP2A诱导的鉴定的信号转导途径和细胞蛋白，目的是抑制与PTLD相关的B细胞淋巴瘤的生长。为了实现这些目标，我们提出了三个具体目标。具体目标1将研究SYK在与PTLD相关的EBV+ B细胞淋巴瘤生存中的需求，并在点头/SCID模型中测试，将SYK作为潜在的治疗策略的价值。具体的目标2将定义PI3K/AKT信号轴的LMP1介导的激活及其在HIL-10诱导中的作用。此外，将测试干预该途径的策略，以作为抑制体内肿瘤生长的一种手段。在特定的目标3中，我们将靶向LMP1诱导的细胞蛋白，以提高宿主CTL消除EBV感染的B细胞淋巴瘤的能力。我们预计这些方法将揭示用于治疗PTLD.7的新颖且有效的治疗选择。 公共卫生相关性：爱泼斯坦Barr病毒相关的B细胞淋巴瘤的发展仍然是严重的，通常是致命的，固体器官和骨髓移植的并发症。目前，尚无既定疗法来治疗这种疾病。因此，识别和定义抑制肿瘤生长的新靶标的研究可能会导致新的诊断和治疗剂预防这种毁灭性疾病。