MECHANISM OF HUMAN LEUKOCYTE CHEMOTAXIS

人类白细胞趋化机制

• 批准号: 3133367
• 负责人: ROBERT D NELSON
• 金额: $ 10.76万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3133367
• 关键词: G protein; burn therapy; chemotaxis; human subject; inflammation; interleukin 2; interleukin 8; monocyte; neoplasm /cancer immunotherapy; neutrophil; protein kinase C; receptor; receptor expression; tumor necrosis factor alpha; tumor necrosis factor beta

Our general objective is to understand mechanisms of control of human neutrophil and monocyte chemotactic function as a component of leukocyte recruitment to sites of inflammation/infection. It applies to two long range goals to know how recruitment of leukocytic phagocytes is normally controlled, and to identify therapy to prevent loss of phagocyte chemotactic function associated with injury, sepsis, or cytokine immunotherapy. Our experimental approach is to identify acquired defects in patient leukocyte chemotaxis and reproduce these defects by various in vitro treatments of control neutrophils to identify inhibitory agents and mechanisms of inhibition. Our working model of mechanisms of leukocyte chemotactic dysfunction in vivo involves altered (i) expression/function of receptors for multiple attractants, (ii) expression of receptors mediating attachment to vascular endothelium, and (iii) components of the cytoskeleton required for motility. Specific aims are based upon our "breakthrough" observation that tumor necrosis factor-alpha (TNF) is a "natural" inhibitor of neutrophil chemotactic sensitivities to multiple attractants. We will apply this observation to studies to identify TNF as the neutrophil chemotaxis inhibitor in patients with thermal injury and patients receiving cytokine immunotherapy (IL-2) for cancer: Aims 1 and 4. Additional experiments will be done to establish the mechanism of TNF-mediated down- regulation of receptors for C5a and IL-8: Aim 2, and the unique ability of TNF to control leukocyte chemotaxis through receptor modulation: Aim 3. Our studies of IL-2 immunotherapy patients are NEW to this proposal and are based upon evidence published by two laboratories during April/May of 1990 that IL-2 infusion produces a neutrophil chemotactic defect associated with significant infectious complications experienced by these patients. Our ability to establish the role of TNF as an inhibitor of leukocyte chemotaxis is based upon a set of criteria describing a "TNF phenotype" derived from studies of control neutrophils treated with TNF in vitro. Measurements of chemoattractant receptors will involve use of fluorescent analogs of FMLP, C5a, and IL-8 and flow cytometry. Eliminating the accumulation or activity of TNF would benefit thermal injury, trauma, and septic patients, as well as patients receiving cytokine immunotherapy. A reagent mimicking this activity of TNF would also be useful therapeutically to limit toxic accumulation of neutrophils in rheumatic, inflammatory bowel, and dermatological diseases and myocardial infarction.

我们的总体目标是了解人类的控制机制 中性粒细胞和单核细胞趋化功能是白细胞的组成部分 招募到炎症/感染部位。它适用于两个长的 了解白细胞吞噬细胞募集正常情况的范围目标 控制，并确定防止吞噬细胞丢失的治疗方法 与损伤、败血症或细胞因子相关的趋化功能 免疫疗法。我们的实验方法是识别获得性缺陷 在患者中白细胞的趋化性并通过不同的方式复制这些缺陷 对照中性粒细胞的体外处理以确定抑制剂 以及抑制机制。我们的机制工作模型 体内白细胞趋化功能障碍涉及改变(I) 多种引诱剂受体的表达/功能(II) 介导血管内皮细胞黏附的受体的表达，以及 (3)运动所需的细胞骨架的组成部分。 具体的目标是基于我们的突破性观察，肿瘤 肿瘤坏死因子是一种天然的中性粒细胞抑制物 对多种引诱剂的趋化敏感性。我们将应用这一点 肿瘤坏死因子作为中性粒细胞趋化作用研究的观察 烧伤患者和接受药物治疗的患者体内的抑制物 癌症的细胞因子免疫治疗(IL-2)：目标1和4。 将进行实验，以建立肿瘤坏死因子介导的降压机制。 C5a和IL-8受体的调节：目标2和独特的能力 肿瘤坏死因子通过受体调节控制白细胞趋化作用：目的 3.我们对IL-2免疫疗法患者的研究是新的 并基于两个实验室在 1990年4月/5月，输注IL-2产生中性粒细胞趋化作用 与重大感染并发症相关的缺陷 被这些病人。 我们确定肿瘤坏死因子作为白细胞抑制因子作用的能力 趋化性是基于一套描述“肿瘤坏死因子表型”的标准。 来源于在体外用肿瘤坏死因子处理的对照中性粒细胞的研究。 化学吸引剂受体的测量将涉及到使用荧光 FMLP、C5a、IL-8类似物和流式细胞术。 消除肿瘤坏死因子的积聚或活性将有利于热疗 损伤、创伤和败血症患者，以及接受 细胞因子免疫疗法。一种模拟这种肿瘤坏死因子活性的试剂 在治疗上也是有用的，可以限制中性粒细胞的毒性积累 风湿性、炎症性肠病和皮肤病 心肌梗死。