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: 7784622
• 负责人: Joel M. Linden
• 金额: $ 48.76万
• 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/7784622
• 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）：我们已经发现cd1d限制性iNKT细胞，一个通常占血液淋巴细胞< 1%的淋巴细胞亚群，在NY1DD镰状细胞小鼠的肺部炎症和损伤的传播中起核心作用。激活后，这些细胞释放IFN和IL-2，引起IFN诱导的趋化因子的产生和循环淋巴细胞上CXCR3的诱导。受体激动剂结合腺苷A2A受体可抑制iNKT细胞的活化。我们已经证明，用抗cd1d抗体选择性阻断iNKT细胞，耗尽它们，或用腺苷A2AR激动剂治疗，可显著减少NY1DD小鼠的基本肺部炎症和损伤。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启动者，建立了镰状细胞肺病的重要新范式。该建议的中心假设是，肺iNKT细胞在响应肺缺血时的激活在通过IFN-和IFN诱导的趋化因子CXCL9 （MIG）和CXCL10 （IP-10）通过CXCR3受体将腺苷敏感的炎症级联从iNKT传播到其他细胞中起关键作用。特异性目标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)缺氧再氧引起的损伤（危象）加重。假设：NKT细胞在持续局灶性肺缺血反应中维持持续的炎症级联反应中起核心作用。iNKT细胞引起广泛的白细胞运输到肺部，最终导致继发性肺损伤。CD1d阻断或CXCR3阻断可减轻SCD肺损伤。特异性目标2将使用：A)淋巴细胞缺陷NY1DD x Rag1 -/-小鼠；B) NY1DD × A2AR-/-小鼠；C) NY1DD x CXCR3 -/-小鼠，作为证实iNKT细胞、A2A受体和CXCR3作为SCD肺损伤介质作用的手段。假设：SCD的肺损伤在很大程度上是由于依赖cxcr3的iNKT细胞募集，而这些细胞是A2A激动剂的关键靶点。特异性Aim 3将评估SCD小鼠和患者血液中iNKT细胞数量、激活状态和CXCR3表达。病人的血液将从我们的合作伙伴，约书亚·菲尔德医生那里运来，他在华盛顿大学经营成人SCD诊所。假设：SCD患者会有iNKT细胞数量、CXCR3表达和细胞内IFN升高，这些升高与疾病严重程度的一些参数相关。