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: 8269732
• 负责人: Joel M. Linden
• 金额: $ 46.03万
• 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/8269732
• 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细胞是一种通常代表血液淋巴细胞<1％的淋巴细胞子集，在NY1DD镰状细胞小鼠中传播肺部炎症和损伤中起着核心作用。激活后，这些细胞释放了IFN和IL-2，从而引起了IFN诱导的趋化因子和CXCR3诱导的产生，并在循环淋巴细胞上诱导。激动剂与腺苷A2A受体结合抑制了inkt细胞的激活。我们已经表明，具有抗CD1D抗体的iNKT细胞的选择性阻断，它们的耗竭或用腺苷A2AR激动剂治疗可显着降低NY1DD小鼠的大量基线肺部炎症和损伤。因此，我们通过表明具有不变T细胞受体（INKT）的NKT细胞是肺损伤的关键启动者，从而建立了镰状细胞肺疾病的重要新范式。该提议的中心假设是，肺INKT细胞响应肺部缺血的激活在传播腺苷敏感的炎症级联反应在从INKT到其他细胞传播IFN和IFN诱导的趋化趋化因子，CXCL9（MIG）（MIG）和CXCL10（IP-10（IP-10））中起着至关重要的作用。具体目标1将：评估抑制Inkt细胞或其CXCR3介导的贩运对A）基线肺部炎症和损伤的后果； b）缺氧 - 抗氧化产生的强调损伤（危机）。假设：NKT细胞在响应持续性局灶性肺部缺血的持续炎症级联反应中起着核心作用。 Inkt细胞唤起了肺部的普通白细胞运输，最终导致继发性肺损伤。 CD1D封锁或CXCR3封锁将减少SCD中的肺损伤。特定的目标2将使用：a）淋巴细胞缺乏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的作用的手段，作为SCD中肺损伤的介体。假设：SCD中的肺损伤很大程度上归因于CXCR3依赖性Inkt细胞的募集，这些细胞是A2A激动剂的关键靶标。特定的目标3将评估小鼠和SCD患者的血液中血液INKT细胞数，激活状态和CXCR3表达。患者的血液将从我们的合作者约书亚·菲尔德（Joshua Field）博士中运送出来，后者在华盛顿大学经营成人SCD诊所。假设：SCD患者的INKT细胞数量升高，CXCR3表达和细胞内IFN与疾病严重程度的某些参数相关。 公共卫生相关性：镰状细胞疾病（SCD）是美国最常见的遗传血液学疾病，影响了约80,000人（每600名非裔美国人中有1人）。它是由2-珠蛋白基因的第六个密码子中的点突变引起的，并导致valine替代谷氨酸残基。 SCD导致多器官衰竭，但肺部特别容易受伤。我们发现，一个较小的淋巴细胞子集，不变的NKT细胞在维持SCD中的肺损伤方面起着重要作用。我们建议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。