Suppression of T cell immunity during sepsis

败血症期间 T 细胞免疫的抑制

• 批准号: 8237299
• 负责人: Thomas S Griffith
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237299
• 关键词: Animals; Antigens; Apoptosis; Apoptotic; Bacteria; Bacterial Infections; CD8B1 gene; Cause of Death; Cell physiology; Cells; Cellular Immunity; Cessation of life; Characteristics; Complex; Data; Defect; Dendritic Cells; Development; Event; Experimental Designs; Failure; Functional disorder; Generations; Goals; Gold; Healthcare; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunization; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Inflammatory Response; Intensive Care Units; Intra-abdominal; Kinetics; Ligation; Link; Lymphoid; Maintenance; Mediating; Memory; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Nature; Nosocomial Infections; Pathogenesis; Patients; Peritonitis; Play; Positioning Attribute; Predisposition; Process; Puncture procedure; Receptor Signaling; Regulation; Role; Secondary to; Sepsis; Signal Pathway; T cell response; T-Lymphocyte; TNF-related apoptosis-inducing ligand; Therapeutic; Veterans; apoptosis in lymphoid cells; base; clinically relevant; combat; design; immune function; in vivo; innovation; mortality; mouse model; novel; prevent; public health relevance; research study; secondary infection; septic

DESCRIPTION (provided by applicant): Sepsis is the leading cause of death in most intensive care units, and the death of septic patients usually does not result from the initial septic event but rather from subsequent nosocomial infections. Patients who survive severe sepsis often display severely compromised immune function. Not only is there significant apoptosis of lymphoid and myeloid cells that depletes critical components of the immune system during sepsis, there is also decreased function of the remaining immune cells. Studies in animals and humans suggest the immune defects that occur during sepsis may be critical to the pathogenesis and subsequent mortality. Using a cecal-ligation and puncture (CLP) model to induce intra-abdominal peritonitis, we recently established a mechanistic link between apoptotic cells generated during sepsis and the establishment of sepsis-induced immune suppression. We also found that the sepsis-induced immune suppression depends on generation of TNF-related apoptosis-inducing ligand (TRAIL)-expressing CD8 T cells. These results suggested TRAIL plays an important role in the induction of sepsis-induced immunosuppression, and we used this information to establish a clinically-relevant "two-hit" model of sepsis, which better reflects the delayed mortality seen during sepsis due to the second infection, to investigate sepsis-induced immune suppression of naove and memory Ag-specific CD8 T cell responses to an experimental secondary bacterial infection. Our proposed experiments will investigate the hypothesis that septic (CLP-treated) mice cannot clear a secondary infection because of the systemic suppression of the T cell compartment that is, in part, mediated by a TRAIL-dependent mechanism. Thus, the following distinct but complementary Specific Aims will be evaluated: 1 - Analyze primary CD8 T cell responses to secondary infection after sepsis and determine the role of TRAIL in sepsis- induced immunosuppression, 2 - Determine the extent to which sepsis influences the function of pre-existing memory CD8 T cells and investigate the role of TRAIL in that process, and 3 - Determine the long lasting consequences of sepsis-induced deletion of naove or memory CD8 T cells in vivo. Our experimental design will allow us to define the cellular and molecular mechanism(s) behind the induction and maintenance of sepsis-induced TRAIL-dependent suppression of T cell immunity. We also expect that the data we obtain from these studies will instrumental in the development of new TRAIL-based therapeutic approaches for counteracting the sepsis-induced immune suppression that leads to the high number of deaths seen during this uncontrolled inflammatory response.

描述（由申请人提供）： 败血症是大多数重症监护病房中死亡的主要原因，化粪池患者的死亡通常不是最初的化粪池事件而导致的，而是由于随后的医院感染而导致的。在严重败血症中存活的患者经常表现出严重损害的免疫功能。不仅存在淋巴样和髓样细胞的明显凋亡，这些细胞会在败血症期间耗尽免疫系统的关键成分，而且其余免疫细胞的功能也降低。对动物和人类的研究表明，败血症期间发生的免疫缺陷可能对发病机理和随后的死亡率至关重要。使用盲肠结扎和穿刺模型（CLP）模型来诱导腹腔内腹膜炎，我们最近建立了败血症期间产生的凋亡细胞与建立败血症诱导的免疫抑制之间的机械联系。我们还发现，败血症诱导的免疫抑制取决于与TNF相关的凋亡诱导配体（TRAIL）表达CD8 T细胞的产生。这些结果表明，TRAIL在诱导败血症诱导的免疫抑制作用中起着重要作用，我们使用这些信息来建立与临床上的败血症相关的“两次冲击”模型，这更好地反映了由于第二种感染而导致的败血症延迟死亡率，研究了SEPSIS诱导的NaOVE抑制NAOVE和Memory Ag Agne Infortional sytrifited CD8 T细胞的免疫抑制作用。 我们提出的实验将研究以下假设：败血症（经CLP处理的）小鼠无法清除继发感染，因为对T细胞区室的系统性抑制部分是由TRAIL依赖性机制介导的。因此，将评估以下不同但互补的特定目的：1-分析败血症后对二次感染的主要CD8 T细胞反应，并确定TRAIL在脓毒症诱导的免疫抑制中的作用，2-确定脓毒症影响到预先存在的记忆CD8 T细胞的功能，并确定该过程中的延长和3的作用 - 持续的过程和3-持续的作用 - CD8 T细胞体内。我们的实验设计将使我们能够在诱导和维持败血症诱导的TRAIL依赖性抑制T细胞免疫的诱导和维持背后定义细胞和分子机制。我们还期望我们从这些研究中获得的数据将有助于开发新的基于步道的治疗方法，以抵消败血症诱导的免疫抑制，从而导致这种不受控制的炎症反应中大量死亡人数。