Molecular Mechanism of Immune Therapy for Bone Marrow Failures

骨髓衰竭免疫治疗的分子机制

• 批准号: 8392110
• 负责人: Pearlie K Burnette
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392110
• 关键词: Acute; Address; Adhesions; Adoptive Transfer; Aftercare; Age; Aging; Animal Model; Animals; Antigens; Antithymoglobulin; Aplastic Anemia; Applications Grants; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Blood; Bone Marrow; Bone Marrow Cells; Bone Marrow Suppression; CD8B1 gene; Caring; Cell Adhesion Molecules; Cells; Cleaved cell; Clinical; Clinical Data; Clinical Research; Complex; Cyclophosphamide; Cyclosporine; Cytolysis; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disease model; Dose; Dysmyelopoietic Syndromes; Effectiveness; Endothelial Cells; Equilibrium; Etiology; Event; Failure; Foundations; Funding; Future; Genetic Transcription; Goals; Hematopoiesis; Home environment; Homing; Immune; Immune response; Immune system; Immunosuppressive Agents; Immunotherapy; In Vitro; Incidence; Individual; Inflammatory; Integrin alpha4beta1; Integrins; L-Selectin; Laboratories; Large granular lymphocyte; Lead; Life Expectancy; Ligands; Link; Lymphocyte; Lymphocyte Homing Receptors; Lymphocytosis; Lymphoid; Manuscripts; Matrix Metalloproteinases; Mediating; Membrane; Metalloproteases; Methotrexate; Modeling; Molecular; Monitor; Mus; Myelogenous; Myelopoiesis; Pancytopenia; Pathogenesis; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Population; Process; Production; Progress Reports; Publishing; Quality of life; Regulation; Rheumatoid Arthritis; Role; SELL gene; Spleen; Surface; Syndrome; System; T-Cell Activation; T-Cell Depletion; T-Lymphocyte; TNF-alpha converting enzyme; Testing; Theophylline; Therapeutic; Therapeutic immunosuppression; Time; Transgenic Mice; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vasculitis; Veterans; Work; abstracting; alpha secretase; base; bone; chronic T-cell leukemia; cytokine; cytopenia; design; effective therapy; improved; in vivo; inhibitor/antagonist; lymph nodes; meetings; migration; mouse model; novel therapeutics; pre-clinical; preclinical study; progenitor; receptor; research study; trafficking; treatment strategy

Abstract: Clonal diseases of large granular lymphocytes (LGL) are characterized by lymphocytosis and T cell-mediated cytopenias of the myeloid compartment. Several syndromes of T cell-mediated bone marrow failure have similar pathology including aplastic anemia (AA), paroxysmal nocturnal hemaglobinuria (PNH), and a subset of patients with Myelodysplastic Syndrome (MDS). All of these syndromes are characterized by clinical improvement with immunosuppressive therapy (IST) such as low-dose methotrexate (MTX), low- dose cyclophosphamide (CY) or cyclosporine A (CyA) and, in the case of aplastic anemia and MDS, T cell depletion with anti-thymocyte globulin (ATG). The broad long-term goal of this proposal is to improve the diagnosis and treatment of patients with LGL leukemia and these other bone marrow failure diseases. In patients with these T-cell mediated bone marrow failure syndromes, it is not clear whether the T lymphocytes become activated locally in the bone marrow against specific bone marrow antigens, or within the peripheral lymphoid system and then home to the bone marrow. The prevailing idea during the last funding period was that an antigen, presumably a common antigen on myeloid progenitors was responsible for suppression of myelopoiesis. This was thought to be due to the direct interaction between this "putative myeloid-specific antigen" and the expanded antigen-specific T cell clone. In the Progress Report, our data strongly suggests that a multi-step model of autoimmunity for this disease process based on work during the last funding period. We show in preliminary results that the lymph node homing receptor L-selectin (CD62L) is dramatically lost from CD8+ T cells in LGL leukemia patients (manuscript published in Blood 2009). The main hypothesis to be addressed in this proposal is that altered bone marrow homing is critical for LGL leukemia pathogenesis. We hypothesize that acute activation in the primary lymphoid system leads to cleavage and shedding of CD62L by the Tumor Necrosis Factor-¿ Converting Enzyme (TACE), which also known as ADAM-17. This matrix metalloproteinase (MMP) cleaves not only CD62L to control the egress of T cells from the lymph node but it is also necessary for the activity of several inflammatory cytokines with known importance in LGL leukemia and other autoimmune diseases. In Specific Aim 1, we will confirm our hypothesis that loss of CD62L expression is mediated primarily by ectodomain shedding by the ADAM-17 matrix metalloproteinase. Because CD62L is a lymphoid homing receptor, we hypothesize that loss of this receptor then allows these activated T cells to exit the lymph node but loss of CD62L alone is not expected to trigger migration and colonization in the bone marrow where these cells suppress hematopoiesis. The focus of Specific Aim 2 is to determine the mechanism of bone marrow homing by T cells in LGL leukemia using an in vitro system. Homing and migration are complex events that are optimally monitored in vivo and there is no mouse model of LGL leukemia or bone marrow failure disease currently available. Moreover, the regulation of homing to the bone marrow even under normal conditions is incompletely understood. Since the antigen that activates T cells in LGL leukemia is unknown, we will use a well defined transgenic mouse model to study important aspects of bone marrow homing and hemosuppression by antigen-specific T cells. This will allow us to test the importance of CD62L, VLA-4, and ADAM-17 in vivo. Additionally, the efficacy of pharmacological inhibitors to block homing to the bone marrow will be tested to provide critical pre-clinical data for application to clinical studies in patients in the future.

摘要：大颗粒状淋巴细胞（LGL）的克隆疾病的特征是淋巴细胞增多和T 细胞介导的髓样室的细胞重皮。 T细胞介导的骨髓的几种综合征 失败具有相似的病理学，包括性障碍（AA），阵发性夜间血红蛋白尿（PNH）， 以及一部分患有骨髓增生综合征（MDS）的患者。所有这些综合征的特征 通过免疫抑制治疗（IST）的临床改善，例如低剂量方法二邻酯（MTX），低 - 剂量环磷酰胺（CY）或环孢霉素A（CYA），如果是塑性性贫血和MDS，则T细胞 抗甲状腺细胞球蛋白（ATG）耗尽。该提议的长期长期目标是改善 LGL白血病患者和其他骨髓衰竭疾病的诊断和治疗。 在患有这些T细胞介导的骨髓衰竭综合征的患者中，尚不清楚T 淋巴细胞在骨髓中局部激活，以针对特定的骨髓抗原或在 周围淋巴系统，然后回到骨髓。最后一个盛行的想法 资金时期是，一种抗原，大概是髓样祖细胞上的常见抗原是负责的 为了抑制骨髓性。这被认为是由于这种“推定的”之间的直接互动 髓样特异性抗原”和扩展的抗原特异性T细胞克隆。在进度报告中，我们的数据 强烈建议，基于此期间的工作，这种疾病过程的自身免疫模型 最后的资金期。我们在初步结果中表明淋巴结归巢接收器l-选择蛋白 （CD62L）在LGL白血病患者的CD8+ T细胞中巨大损失（手稿发表在血液中 2009）。该提案中要解决的主要假设是改变的骨髓归巢是 LGL白血病发病机理至关重要。我们假设在原发性淋巴机中急性激活 系统导致肿瘤坏死因子对CD62L的切割和脱落 - 转化酶 （TACE），也称为Adam-17。该基质金属蛋白酶（MMP）不仅裂解CD62L 控制T细胞从淋巴结的出口，但也需要几个活性 在LGL白血病和其他自身免疫性疾病中，炎性细胞因子具有已知重要性。在 具体目的1，我们将确认我们的假设，即CD62L表达的丧失是由 ADAM-17基质金属蛋白酶脱落的外生域脱落。因为CD62L是淋巴样 受体，我们假设该受体的丧失允许这些活化的T细胞退出淋巴 节点，但仅预计单独的CD62L损失就不会触发骨髓中的迁移和定植 这些细胞抑制造血。特定目标2的重点是确定 使用体外系统，T细胞在LGL白血病中的骨髓归巢。归宿和迁移是 在体内最佳监测的复杂事件，没有LGL白血病或骨的小鼠模型 目前可用的骨髓衰竭疾病。此外，即使 在正常情况下，不完全理解。由于激活LGL中T细胞的抗原 白血病是未知的，我们将使用定义明确的转基因小鼠模型来研究 抗原特异性T细胞的骨髓归巢和抑制。这将使我们能够测试 在体内CD62L，VLA-4和ADAM-17的重要性。另外，药物抑制剂的效率 将测试阻止归巢的骨髓，以提供关键的临床前数据以应用于 将来对患者的临床研究。