Lymphocyte Activation in Sickle Cell Lung Disease

镰状细胞性肺病中的淋巴细胞激活

• 批准号: 8067086
• 负责人: Joel M. Linden
• 金额: $ 46.52万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067086
• 关键词: Acute; Adenosine; Adenosine A2A Receptor; Adhesions; Adoptive Transfer; Adult; Affect; African American; Agonist; Antibodies; Antigen Presentation; Antigens; Binding; Blood; Blood Platelets; Blood capillaries; Bone Marrow; CXC chemokine receptor 3; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cell Count; Cells; Clinic; Clinical; Coagulation Process; Codon Nucleotides; Data; Disease; Endothelium; Generations; Genes; Genetic; Globin; Glutamic Acid; Hematological Disease; Hypoxia; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferons; Interleukin-2; Interleukin-4; Investigation; Ischemia; Leukocyte Chemotaxis; Leukocyte Trafficking; Leukocytes; Ligands; Lipids; Lung; Lung diseases; Lymphocyte; Lymphocyte Activation; Lymphocyte Subset; Mature Lymphocyte; Mediating; Mediator of activation protein; Messenger RNA; Minor; Mus; Natural Killer Cells; Organ failure; Patients; Play; Pneumonia; Point Mutation; Population; Production; Rag1 Mouse; Receptor Activation; Recurrence; Reperfusion Injury; Reperfusion Therapy; Role; Running; Scheme; Severity of illness; Shipping; Ships; Sickle Cell; Sickle Cell Anemia; T-Cell Receptor; Tissues; United States; Universities; Valine; Vascular Endothelium; Washington; bone; capillary; cell type; chemokine; injured; lard; lung injury; lung ischemia; neutrophil; public health relevance; receptor; response; trafficking; vascular inflammation

DESCRIPTION (provided by applicant): We have discovered that CD1d-restricted iNKT cells, a lymphocyte subset that normally represents < 1% of blood lymphocytes, plays a central role in propagating pulmonary inflammation and injury in the NY1DD sickle cell mouse. Upon activation, these cells release IFN and IL-2 which evoke the production of IFN-inducible chemokines and CXCR3 induction on circulating lymphcytes. iNKT cell activation is inhibited by agonist binding to adenosine A2A receptors. We have shown that selective blockade of iNKT cells with anti-CD1d antibodies, their depletion, or treatment with an adenosine A2AR agonist, significantly reduces substantial baseline pulmonary inflammation and injury in NY1DD mice. Thus, we have established an important new paradigm of sickle cell lung disease by showing that NKT cells that have an invariant T cell receptor (iNKT) are key initiators of lung injury. The central hypothesis of this proposal is that activation of pulmonary iNKT cells in response to lung ischemia plays a critical role in propagating an adenosine-sensitive inflammatory cascade from iNKT to other cells by IFN- and IFN-inducible chemokines, CXCL9 (MIG) and CXCL10 (IP-10) via CXCR3 receptors. Specific Aim 1 will: assess the consequences of inhibiting iNKT cells or their CXCR3-mediated trafficking on A) baseline pulmonary inflammation and injury; B) accentuated injury (crisis) produced by hypoxia-reoxygenation. Hypothesis: NKT cells play a central role in maintaining an ongoing inflammatory cascade in response to persistent focal lung ischemia. iNKT cells evoke generalized leukocyte trafficking to the lung that ultimately results in secondary lung injury. CD1d blockade or CXCR3 blockade will reduce lung injury in SCD. Specific Aim 2 will use: A) lymphocyte deficient NY1DD x Rag1 -/- mice; B) NY1DD x A2AR-/- mice; and C) NY1DD x CXCR3 -/- mice, as means of substantiating the roles of iNKT cells, A2A receptors and CXCR3 as mediators of lung injury in SCD. Hypothesis: Lung injury in SCD is due in large part to CXCR3-dependent iNKT cell recruitment and these cells are key targets of A2A agonists. Specific Aim 3 will assess blood iNKT cell numbers, activation state and CXCR3 expression in the blood of mice and patients with SCD. Patient blood will be shipped from our collaborator, Dr. Joshua Field, who runs the adult SCD clinic at Washington University. Hypothesis: Patients with SCD will have elevated iNKT cell numbers, CXCR3 expression and intracellular IFN that will be correlated to some parameters of disease severity. PUBLIC HEALTH RELEVANCE: Sickle cell disease (SCD) is the most common genetic hematological disorder in the United States, affecting about 80,000 people (1 of every 600 African Americans). It is caused by a point mutation in the sixth codon of the 2-globin gene, and results in replacement of a glutamic acid residue by valine. SCD leads to multi-organ failure, but the lungs are particularly susceptible to injury. We have discovered that a minor lymphocyte subset, invariant NKT cells play an important role in maintaining lung injury in SCD. We propose to investigate how this cells produces lung injury, and the effects of inhibiting its function on lung injury. We also will study iNKT cells in the blood of SCD patients.

描述（由申请人提供）：我们发现 CD1d 限制性 iNKT 细胞（通常占血液淋巴细胞的 1% 以下）的淋巴细胞亚群，在 NY1DD 镰状细胞小鼠肺部炎症和损伤的传播中发挥着核心作用。激活后，这些细胞释放 IFN 和 IL-2，从而引起 IFN 诱导趋化因子的产生以及循环淋巴细胞上 CXCR3 的诱导。 iNKT 细胞活化受到与腺苷 A2A 受体结合的激动剂的抑制。我们已经证明，用抗 CD1d 抗体选择性阻断 iNKT 细胞、消除它们或用腺苷 A2AR 激动剂治疗，可显着减少 NY1DD 小鼠的基线肺部炎症和损伤。因此，我们通过证明具有不变 T 细胞受体 (iNKT) 的 NKT 细胞是肺损伤的关键启动子，建立了镰状细胞性肺病的重要新范例。该提案的中心假设是，肺缺血时肺 iNKT 细胞的激活在 IFN 和 IFN 诱导趋化因子 CXCL9 (MIG) 和 CXCL10 将腺苷敏感炎症级联从 iNKT 传播到其他细胞中发挥着关键作用。 (IP-10) 通过 CXCR3 受体。具体目标 1 将：评估抑制 iNKT 细胞或其 CXCR3 介导的运输对 A) 基线肺部炎症和损伤的影响； B) 缺氧-复氧造成的严重损伤（危机）。假设：NKT 细胞在维持持续的炎症级联反应以应对持续性局灶性肺缺血方面发挥着核心作用。 iNKT 细胞引起全身白细胞转运至肺部，最终导致继发性肺损伤。 CD1d 阻断或 CXCR3 阻断将减少 SCD 中的肺损伤。具体目标 2 将使用：A) 淋巴细胞缺陷的 NY1DD x Rag1 -/- 小鼠； B) NY1DD x A2AR-/- 小鼠； C) NY1DD x CXCR3 -/- 小鼠，作为证实 iNKT 细胞、A2A 受体和 CXCR3 作为 SCD 肺损伤介质的作用的手段。假设：SCD 中的肺损伤很大程度上是由于 CXCR3 依赖性 iNKT 细胞招募所致，这些细胞是 A2A 激动剂的关键靶点。具体目标 3 将评估小鼠和 SCD 患者血液中的 iNKT 细胞数量、激活状态和 CXCR3 表达。患者的血液将从我们的合作者 Joshua Field 博士那里运来，他在华盛顿大学经营成人 SCD 诊所。假设：SCD 患者的 iNKT 细胞数量、CXCR3 表达和细胞内 IFN 升高，这与疾病严重程度的某些参数相关。 公众健康相关性：镰状细胞病 (SCD) 是美国最常见的遗传性血液病，影响约 80,000 人（每 600 名非裔美国人中就有 1 人）。它是由 2-珠蛋白基因第六个密码子的点突变引起的，导致谷氨酸残基被缬氨酸取代。 SCD 会导致多器官衰竭，但肺部特别容易受伤。我们发现，少数淋巴细胞亚群、不变的 NKT 细胞在维持 SCD 肺损伤方面发挥着重要作用。我们建议研究这种细胞如何产生肺损伤，以及抑制其功能对肺损伤的影响。我们还将研究 SCD 患者血液中的 iNKT 细胞。