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）：移植后淋巴组织增生性疾病（PTLD）描述了实体器官和骨髓移植的形态异质性并发症，范围从良性 B 细胞增生到恶性淋巴瘤。 PTLD 的标志是 Epstein Barr 病毒 (EBV) 相关 B 细胞淋巴瘤的发展。目前，PTLD 尚无成熟的治疗方法，报告的死亡率通常超过 50%。已采用多种策略来治疗 PTLD 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））和过继性细胞免疫疗法。然而，这些方法都有明显的局限性。我们广泛的长期目标是确定对 PTLD 相关 EBV+ B 细胞淋巴瘤生长和生存至关重要的细胞和病毒蛋白，旨在确定治疗靶向的新候选药物。我们假设 EBV 选择宿主细胞途径来促进 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，通过该途径，潜伏周期 EBV 蛋白、潜伏膜蛋白 1 (LMP1) 诱导受感染 B 细胞中人 IL-10 (hIL-10) 的产生。 hIL-10 在多种 EBV+ 相关恶性肿瘤（包括 PTLD）中充当有效的自分泌生长因子。我们还确定，由病毒蛋白潜伏膜蛋白 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 的小分子抑制剂可显着抑制 PTLD 衍生细胞系的生长和存活。最后，我们证明 LMP1 通过 NF:B 依赖性途径，赋予对 CTL 和 NK 细胞用来消除病毒感染和转化细胞的关键死亡受体 (DR) 效应机制的抗性，从而破坏宿主免疫。我们的研究结果表明细胞蛋白 cFLIP 与 DR 诱导的细胞凋亡的抵抗有关。在本提案中，我们将针对由关键病毒蛋白 LMP1 和 LMP2a 诱导的已识别信号转导途径和细胞蛋白，以抑制 PTLD 相关 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 PTLD 相关 EBV+ B 细胞淋巴瘤生存中对 Syk 的需求，并在 NOD/SCID 模型中测试以 Syk 为目标的潜在治疗策略的价值。具体目标 2 将定义 LMP1 介导的 PI3K/AKT 信号轴激活及其在 hIL-10 诱导中的作用。此外，将测试干预该途径的策略作为抑制体内肿瘤生长的手段。在具体目标 3 中，我们将靶向 LMP1 诱导的细胞蛋白 cFLIP，旨在增强宿主 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治疗 PTLD.7 的新颖且有效的治疗选择。 公共卫生相关性：EB 病毒相关 B 细胞淋巴瘤的发展仍然是实体器官和骨髓移植的严重且通常致命的并发症。目前，还没有治疗这种疾病的既定疗法。因此，识别和定义抑制肿瘤生长的新靶点的研究可能会产生新的诊断和治疗药物来预防这种破坏性疾病。