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，CD 1d限制性iNKT细胞（一种通常占血液淋巴细胞< 1%的淋巴细胞亚群）在NY 1DD镰状细胞小鼠中传播肺部炎症和损伤中发挥重要作用。在活化后，这些细胞释放IFN和IL-2，其引起IFN诱导型趋化因子的产生和循环淋巴细胞上的CXCR 3诱导。iNKT细胞活化通过与腺苷A2 A受体结合的激动剂抑制。我们已经证明，用抗CD 1d抗体选择性阻断iNKT细胞，耗尽它们，或用腺苷A2 AR激动剂治疗，显著降低了NY 1DD小鼠的基线肺部炎症和损伤。因此，我们通过显示具有不变T细胞受体（iNKT）的NKT细胞是肺损伤的关键起始物，建立了镰状细胞肺病的重要新范例。该提议的中心假设是，响应于肺缺血的肺iNKT细胞的活化在通过IFN-和IFN-诱导型趋化因子CXCL 9（CXCL 9）和CXCL 10（IP-10）经由CXCR 3受体将腺苷敏感性炎症级联从iNKT传播到其他细胞中起关键作用。具体目标1将：评估抑制iNKT细胞或其CXCR 3介导的运输对A）基线肺部炎症和损伤的后果; B）缺氧-复氧产生的加重损伤（危象）。假设：NKT细胞在维持持续局灶性肺缺血的持续炎症级联反应中发挥重要作用。iNKT细胞引起全身性白细胞运输至肺，最终导致继发性肺损伤。阻断CD 1d或CXCR 3可减轻SCD患者的肺损伤。具体目标2将使用：用途：A）淋巴细胞缺陷型NY 1DD x Rag 1-/-小鼠; B）NY 1DD x A2 AR-/-小鼠;和C）NY 1DD x CXCR 3-/-小鼠，作为证实iNKT细胞、A2 A受体和CXCR 3作为SCD中肺损伤介质的作用的手段。假设：SCD中的肺损伤在很大程度上是由于CXCR 3依赖性iNKT细胞募集，并且这些细胞是A2 A激动剂的关键靶标。具体目标3将评估血液iNKT细胞数量、活化状态和SCD小鼠和患者血液中的CXCR 3表达。病人的血液将由我们的合作者约书亚菲尔德博士运送，他在华盛顿大学经营成人SCD诊所。假设：患有SCD的患者将具有升高的iNKT细胞数量、CXCR 3表达和细胞内IFN，其将与疾病严重程度的一些参数相关。 公共卫生关系：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名非洲裔美国人中有1人）。它是由2-珠蛋白基因第六密码子的点突变引起的，并导致谷氨酸残基被缬氨酸取代。SCD导致多器官衰竭，但肺部特别容易受伤。我们已经发现，一个小的淋巴细胞亚群，不变的NKT细胞在维持SCD肺损伤中起重要作用。我们拟研究该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。