MECHANISMS OF IMMUNOSUPPRESSION IN SEPSIS

脓毒症的免疫抑制机制

• 批准号: 8297918
• 负责人: Jonathan M. Green
• 金额: $ 57.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-07 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297918
• 关键词: Activities of Daily Living; Animal Model; Autopsy; Blood; CTLA4 gene; Cells; Cessation of life; Chronic; Coupled; Data; Defect; Development; Disease; Enrollment; Functional disorder; Gene Expression; Goals; Hour; Immune; Immune System and Related Disorders; Immune system; Immunocompetent; Immunosuppression; Infection; Intensive Care Units; Lung; Organism; Pathogenesis; Patient Care; Patients; Pattern; Phase; Phenotype; Population; Prospective Studies; Risk; Sampling; Sepsis; Spleen; Staging; T-Lymphocyte; Time; Virus Diseases; clinically relevant; exhaust; exhaustion; immunosuppressed; interest; mortality; novel; receptor; response; secondary infection

DESCRIPTION (provided by applicant): Sepsis is a systemic response to severe infection with an associated mortality of approximately 30%. Although many sepsis-induced deaths take place during the initial hyperinflammatory phase, those patients that survive often develop and may succumb to secondary infections. These infections are frequently caused by organisms not typically pathogenic in immunocompetent hosts, suggesting that this later phase of sepsis is characterized by clinically important immunosuppression. Although a number of mechanisms of immunosuppression have been identified in animal models of sepsis, few systematic studies have been conducted in patients. In addition, relatively new and potent mechanisms involving expression of inhibitory receptors such as PD-1, BTLA and CTLA4, as well as regulatory cell populations have been identified. Of particular interest, patients with chronic viral infection hav been demonstrated to develop a phenomenon termed immune cell exhaustion. Characterized by persistent, elevated expression of inhibitory receptors, exhausted T cells manifest severe functional defects. Supported by our preliminary data, we hypothesize that the immunosuppression in sepsis results from the combined consequences of an expansion of suppressive cells and a state of immune cell exhaustion that develops progressively over time, such that at early stages it is both identifiable and reversible. The goals of this project are to ) determine the mechanism of immunosuppression in patients that die of sepsis, and 2) identify clinically relevant markers that identify those patients with sepsis that are immunosuppressed and for which immunomodulating therapies may be of benefit. To achieve these goals, we will perform a detailed functional, phenotypic and mechanistic analysis of immune cells isolated following a novel, rapid bedside autopsy of patients that die of sepsis. This will be coupled with a prospective study of patients hospitalized in the intensive care units with sepsis, to determine clinically useful markers that can identify patients that are more severely immune compromised and therefore at increased risk for secondary infection. Together, these studies will substantially advance our understanding of the pathogenesis of this disease and directly impact the care of patients with sepsis. PUBLIC HEALTH RELEVANCE: This study will examine the reasons why patients with sepsis die. In particular, the study will examine mechanisms for the impaired immune system that occurs in patients with prolonged sepsis.

描述（由申请人提供）：败血症是对严重感染的系统反应，相关死亡率约为30％。尽管许多败血症诱发的死亡发生在初始高炎性阶段，但生存的患者经常发育并可能屈服于继发性感染。这些感染通常是由免疫能力宿主通常不致病的生物引起的，这表明败血症的后期阶段的特征是临床上重要的免疫抑制。尽管在败血症的动物模型中已经发现了许多免疫抑制的机制，但在患者中很少进行系统研究。此外，已经确定了涉及抑制性受体（例如PD-1，BTLA和CTLA4）以及调节细胞种群的相对较新和有效的机制。特别感兴趣的是，慢性病毒感染的患者被证明会形成一种称为免疫细胞疲劳的现象。耗尽的T细胞以持续的，抑制受体的表达持续，表达升高，表现出严重的功能缺陷。在我们的初步数据的支持下，我们假设败血症中的免疫抑制是由于抑制细胞扩张的综合后果以及随着时间的推移而逐渐发展的免疫细胞衰竭状态，因此在早期阶段，它既可以识别又可逆。该项目的目标是）确定死于败血症患者的免疫抑制的机制，以及2）识别临床相关标记，这些标志是识别那些败血症患者免疫抑制的患者，并且免疫调节疗法可能有益。为了实现这些目标，我们将对在新型败血症患者的新型，快速的床边尸检后，对分离的免疫细胞进行详细的功能，表型和机械分析。这将与对患有败血症的重症监护病房住院的患者的前瞻性研究相结合，以确定可以识别更严重免疫受到损害的患者，因此患有继发感染的风险增加。这些研究将大大将 促进我们对这种疾病发病机理的理解，并直接影响败血症患者的护理。 公共卫生相关性：这项研究将研究败血症患者死亡的原因。特别是，该研究将检查长期败血症患者发生的免疫系统受损的机制。