Immature Myeloid Cells and T Cell Suppression in Trauma

创伤中的未成熟骨髓细胞和 T 细胞抑制

• 批准号: 7389008
• 负责人: Juan B. Ochoa
• 金额: $ 23.46万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389008
• 关键词: Amino Acids; Arginine; Basic Amino Acid Transport Systems; CD14 gene; Catecholamines; Cell membrane; Cell physiology; Cells; Cessation of life; Characteristics; Citrulline; Data; Dendritic Cells; Dinoprostone; Exhibits; FCGR3B gene; Functional disorder; Goals; Guanine Nucleotide Dissociation Inhibitors; Hospitals; Host Defense; Hour; Immune System Diseases; Immune response; Infection; Injury; Interferon Gamma/Interleukin-2; Interferons; Interleukin-10; Interleukin-13; Interleukin-2; Interleukin-4; Laboratories; Lead; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Nature; Numbers; Operative Surgical Procedures; Outcome; PTPRC gene; Patients; Peptides; Population; Production; Risk; Role; Secondary to; Sepsis; Severities; Signal Transduction; Spleen; Stress; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Trauma; Up-Regulation; arginase; base; cost; cytokine; design; immune function; monocyte; mortality; novel; prevent; uptake

DESCRIPTION (provided by applicant): Impaired host responses after trauma or surgery (traumatic stress) render patients susceptible to sepsis thus greatly increasing morbidity, mortality and cost. T cell dysfunction is central to impaired host defenses after traumatic stress and is characterized by decreased proliferation, and production of cytokines (Interleukin 2 and interferon gamma) and a decrease in the number of T cell receptors (TCR) expressed on the cell membrane as a result of decreased L, chain. Myeloid cells are known to cause T cell dysfunction in traumatic stress, but the nature of these cells and how they cause T cell dysfunction is unclear. Our laboratory has recently found that traumatic stress induces the activation of a distinct immature myeloid cell population expressing both CD1 lb+ and GR1+ markers. These cells infiltrate the marginal zones of the spleen within 6 hours after trauma and by 12 hours constitute up to 15% of all spleen cells. Trauma-induced immature myeloid GDI lb+/GR-l+ cells (TIIMC) decrease T cell proliferation, impair cytokine production and decrease TCR zeta, chain expression. TIIMC also express very high levels of arginase 1 (ARG1) and possibly the cationic aminoacid transporter Cat2b and therefore appear to deplete arginine, an amino acid necessary for T cell function. Based on these observations we hypothesize that traumatic stress generates specific signals which induce arginase 1 expression in a distinct immature myeloid cell population that can alter T-cell function through arginine depletion. Our goals are to determine the mechanisms by which ARG1 in TIIMC causes T cell dysfunction, to identify the signals that induce and sustain the production of ARG1 in TIMC and to develop strategies designed to block or overcome T cell dysfunction after traumatic stress. We will answer these questions using a highly reproducible model of traumatic stress, in which ARG1 production is proportional to the severity of injury. We believe that the identification of an immature myeloid cell in a murine model of trauma is a novel observation that will allow us to understand T cell dysfunction in trauma and evaluate therapeutic strategies with translational potential.

描述（由申请人提供）： 创伤或手术后的宿主反应受损（创伤性压力）使患者容易受到败血症的影响，从而大大提高了发病率，死亡率和成本。 T细胞功能障碍是创伤应力后宿主防御受损的核心，其特征是增殖降低，细胞因子的产生（白介素2和干扰素γ）和T细胞受体数量（TCR）减少，在细胞膜上表达为L，链减少的结果。已知髓样细胞在创伤性应激中引起T细胞功能障碍，但是这些细胞的性质以及它们如何引起T细胞功能障碍尚不清楚。我们的实验室最近发现，创伤应力诱导表达CD1 LB+和GR1+标记的独特的未成熟髓样细胞群的激活。这些细胞在创伤后6小时内渗入脾脏的边际区域，到12小时，最多占所有脾细胞的15％。创伤引起的未成熟髓样GDI LB+/GR-L+细胞（TIIMC）减少T细胞增殖，损害细胞因子的产生并降低TCR Zeta，链表达。 TIIMC还表达了非常高的精氨酸酶1（ARG1），也可能是阳离子氨基酸转运蛋白Cat2b，因此似乎耗尽了精氨酸，这是T细胞功能所需的氨基酸。基于这些观察结果，我们假设创伤应力会产生特定的信号，这些信号在不同的未成熟髓样细胞群中诱导精氨酸酶1的表达，可以通过精氨酸消耗来改变T细胞功能。我们的目标是确定TIIMC中ARG1导致T细胞功能障碍的机制，以确定诱导和维持TIMC中ARG1产生的信号，并制定旨在阻止或克服创伤性压力后T细胞功能障碍的策略。我们将使用高度可重复的创伤压力模型回答这些问题，其中ARG1的产生与伤害的严重程度成正比。我们认为，在鼠创伤的鼠模型中鉴定出未成熟的髓样细胞是一种新颖的观察结果，它将使我们能够理解创伤中的T细胞功能障碍，并评估具有转化潜力的治疗策略。