MECHANISM OF HUMAN LEUKOCYTE CHEMOTAXIS

人类白细胞趋化机制

• 批准号: 3133368
• 负责人: ROBERT D NELSON
• 金额: $ 12.98万
• 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/3133368
• 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作为白细胞组分 募集至炎症/感染部位。 它适用于两个长 目的是了解白细胞吞噬细胞的募集通常是如何进行的。 控制，并确定治疗，以防止损失的吞噬细胞 与损伤、脓毒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后天缺陷 在患者中，白细胞趋化性并通过各种途径复制这些缺陷 对照中性粒细胞的体外处理以鉴定抑制剂 和抑制机制。 我们的工作模型 体内白细胞趋化性功能障碍涉及改变（i） 多种引诱剂受体的表达/功能，（ii） 介导与血管内皮附着的受体的表达，和 (iii)运动所需的细胞骨架成分。 具体目标是基于我们的“突破性”观察， 坏死因子-α（TNF）是中性粒细胞的“天然”抑制剂， 对多种引诱剂的趋化敏感性。 我们将应用这个 观察研究，以确定TNF作为中性粒细胞趋化性 抑制剂在热损伤患者和接受 癌症的细胞因子免疫疗法（IL-2）：目的1和4。额外 将进行实验以建立TNF介导的下调- C5 a和IL-8受体的调节：目的2，以及 TNF通过受体调节控制白细胞趋化性：目的 3. 我们对IL-2免疫治疗患者的研究是这一提议的新内容 并基于两个实验室发表的证据， 1990年4月/5月，IL-2输注产生中性粒细胞趋化性 与严重感染并发症相关的缺陷 这些患者。 我们能够确定TNF作为白细胞抑制剂的作用， 趋化性是基于一组描述“TNF表型”的标准 来源于体外TNF处理的对照中性粒细胞的研究。 化学引诱物受体的测量将涉及使用荧光标记。 FMLP类似物、C5 a和IL-8以及流式细胞术。 消除TNF的积累或活性将有利于热 受伤、创伤和败血症患者，以及接受 细胞因子免疫疗法 模拟TNF这种活性的试剂将 在治疗上也可用于限制嗜中性粒细胞的毒性积聚 风湿性、炎症性肠病和皮肤病， 心肌梗死