IMMUNOLOGIC BASIS FOR SUSCEPTIBILITY TO SECONDARY INFECTIONS IN SEVERE SEPSIS

严重脓毒症继发感染易感性的免疫学基础

• 批准号: 8008689
• 负责人: Jonathan M. Green
• 金额: $ 22.8万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8008689
• 关键词: Acute; Affect; Animal Model; Antibiotics; Apoptotic; Biological Markers; Blood; CTLA4 gene; Cancer Patient; Cause of Death; Cell Death; Cell physiology; Cells; Clinical; Clinical Trials; Critical Illness; Data; Defect; Defense Mechanisms; Dioxygenases; Disease; Environment; Generations; Goals; Hospitals; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunologics; Immunosuppression; Immunosuppressive Agents; Infection; Intervention; Intervention Trial; Irrigation; Ligands; Lower Respiratory Tract Infection; Lung; Lymphocyte; Lymphocyte Function; Lymphoid; Lymphoid Cell; Measures; Mechanics; Mediating; Metabolic Pathway; Morbidity - disease rate; Myelogenous; Myeloid Cells; Nature; Nosocomial Infections; Pathway interactions; Patient Selection; Patients; Pattern; Peripheral Blood Lymphocyte; Phase; Play; Pneumonia; Population; Predisposition; Prevention; Principal Investigator; Randomized; Regulatory T-Lymphocyte; Relative (related person); Risk; Risk Factors; Role; Sepsis; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Testing; Therapeutic; Time; Ventilator; Work; base; cell type; cost; follower of religion Jewish; immune function; immunosuppressed; improved; indoleamine; mortality; novel; novel therapeutic intervention; peripheral blood; prevent; protein expression; public health relevance; receptor; receptor expression; secondary infection; septic; therapy design

DESCRIPTION (provided by applicant): Over 200,000 people die annually in the US from the consequences of sepsis. While molecularly guided therapy has been introduced for many diseases, such interventions remain elusive in the treatment of sepsis. Many patients that survive the acute phase of sepsis develop secondary infections and succumb to these later complications. The majority of septic patients are mechanically ventilated, and sepsis is an independent risk factor for ventilator associate pneumonia (VAP). VAP is the most common nosocomial infection in the ICU, is responsible for the majority of ICU antibiotic use and carries a mortality of close to 40%. While factors that interrupt normal upper airway defense mechanisms are important contributors, host immune factors likely play an equally critical role. The identification of these factors is a major goal this proposal. Importantly, these pathways may offer novel opportunities for therapeutic manipulation. Recent work has documented a state of relative immunosuppression occurring in both animal models and humans with sepsis. Apoptotic cell death of lymphocytes as well as a defect in the function of the remaining cells has been demonstrated, of which the underlying mechanism has not been determined. Prevention or reversal of this immunosuppression would be predicted to prevent many of the later sequelae of sepsis and thereby improve patient survival. During a normal immune response lymphocyte function is restricted by specific receptor mediated, inhibitory signaling pathways and by the action of distinct cell types including regulatory T (Treg) cells and myeloid derived suppressor cells (MDSC). We hypothesize that in sepsis there is an inappropriate, widespread induction of suppressive pathways resulting in the active inhibition of T cell function. We propose that increased expression of inhibitory receptors on peripheral blood lymphocytes and/or an increase in suppressor cell populations (Tregs and MDSCs) will identify and differentiate those patients at increased risk of secondary infection from those not at risk, and thereby serve as a "biomarker" allowing for targeted therapies. We also propose that the susceptibility to VAP is driven by the parenchymal cells of the lung. By expressing specific inhibitory ligands and metabolic pathways such as indoleamine 2,3 dioxygenase (IDO), the lung parenchyma creates an immunosuppressive environment that actively inhibits lymphocyte function. We propose to test this hypothesis by characterizing the blood and lung cells from with patients sepsis that develop VAP admitted to the ICU's at Barnes-Jewish Hospital. While exploratory, these studies have the potential to be paradigm shifting and lay the groundwork for novel therapeutic interventions in sepsis. Currently biologics that manipulate CTLA4, PD-1 and IDO signaling are in clinical trials as immune modulating agents in cancer patients. The results of this study will allow for the clinical identification of immunosuppressed patients at risk for infection, as well as provide preliminary data in support of a larger, definitive trial with the eventual goal of a randomized intervention trial. PUBLIC HEALTH RELEVANCE: This proposal aims to understand the reason for the suppressed immune response in critically ill patients. The relative immunosuppressed state in these patients often results in infections that are the cause of death. The studies we propose in this application will allow us to identify patients at risk for infection, and design treatments to enhance their immune function.

描述（由申请人提供）：美国每年都会因败血症的后果而在美国死亡。尽管已经针对许多疾病引入了分子引导的疗法，但这种干预措施在败血症的治疗中仍然难以捉摸。许多在脓毒症急性期生存的患者会产生继发性感染并屈服于这些后来的并发症。大多数化粪池患者是机械通气的，败血症是呼吸机副肺炎（VAP）的独立危险因素。 VAP是ICU中最常见的医院感染，是造成大多数ICU抗生素使用的原因，死亡率接近40％。虽然中断正常呼吸道防御机制的因素是重要的因素，但宿主免疫因素可能同样至关重要。这些因素的识别是该建议的主要目标。重要的是，这些途径可能为治疗操作提供新的机会。 最近的工作记录了动物模型和败血症人类中发生的相对免疫抑制的状态。已经证明了淋巴细胞的凋亡细胞死亡以及其余细胞功能的缺陷，尚未确定基本机制。预测这种免疫抑制的预防或逆转将被预测可预防许多后来的败血症后遗症，从而改善患者的生存率。在正常的免疫反应期间，淋巴细胞功能受到特定受体介导的抑制性信号通路的限制，并受到不同细胞类型的作用，包括调节t（Treg）细胞和髓样衍生的抑制细胞（MDSC）。我们假设在败血症中存在不适当的，广泛的抑制途径，导致T细胞功能的主动抑制。我们建议，抑制性受体在外周血淋巴细胞上的表达增加和/或抑制细胞群体（Tregs和MDSCS）的增加将识别并区分那些患有继发感染风险的患者与不处于风险的患者增加，从而成为“生物标志物”，从而允许靶向治疗。我们还建议对VAP的敏感性由肺实质细胞驱动。通过表达特定的抑制性配体和代谢途径，例如吲哚胺2,3二加氧酶（IDO），肺实质会产生一种免疫抑制环境，从而积极抑制淋巴细胞功能。我们建议通过表征来自Barnes-Jewish医院ICU的患者的败血症患者的血液和肺细胞来检验这一假设。在探索性的同时，这些研究有可能是范式转移，并为败血症的新治疗干预奠定了基础。目前，操纵CTLA4，PD-1和IDO信号传导的生物制剂正在临床试验中，作为癌症患者的免疫调节剂。这项研究的结果将允许对感染风险的免疫抑制患者进行临床鉴定，并提供初步数据，以支持更大，确定的试验，并最终进行随机干预试验。 公共卫生相关性：该提案旨在了解重症患者免疫反应的原因。这些患者的相对免疫抑制状态通常会导致死亡原因。我们在本应用中提出的研究将使我们能够鉴定出感染风险的患者，并设计治疗以增强其免疫功能。