Suppression of T cell immunity during sepsis

败血症期间 T 细胞免疫的抑制

• 批准号: 8601255
• 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/8601255
• 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）： 脓毒症是大多数重症监护病房的主要原因，脓毒症患者的死亡通常不是由最初的脓毒症事件引起，而是由随后的院内感染引起。严重脓毒症幸存的患者通常表现出严重受损的免疫功能。在脓毒症期间，不仅淋巴和骨髓细胞显着凋亡，耗尽免疫系统的关键成分，而且剩余免疫细胞的功能也会下降。对动物和人类的研究表明，脓毒症期间发生的免疫缺陷可能对发病机制和随后的死亡率至关重要。利用盲肠结扎穿刺（CLP）模型诱导腹内腹膜炎，我们最近在脓毒症期间产生的凋亡细胞与脓毒症诱导的免疫抑制的建立之间建立了机制联系。我们还发现脓毒症诱导的免疫抑制取决于表达 TNF 相关凋亡诱导配体 (TRAIL) 的 CD8 T 细胞的产生。这些结果表明TRAIL在脓毒症引起的免疫抑制的诱导中发挥着重要作用，我们利用这些信息建立了临床相关的脓毒症“二次打击”模型，该模型更好地反映了脓毒症期间由于第二次攻击而导致的延迟死亡率。感染，以研究脓毒症诱导的免疫抑制对实验性继发性细菌感染的幼稚和记忆 Ag 特异性 CD8 T 细胞的反应。 我们提出的实验将调查以下假设：脓毒症（CLP 处理的）小鼠无法清除继发感染，因为 T 细胞区室受到系统性抑制，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具体目标： 1 - 分析脓毒症后继发性感染的原代 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 - 确定脓毒症影响免疫功能的程度预先存在的记忆 CD8 T 细胞并研究 TRAIL 在该过程中的作用，以及 3 - 确定脓毒症诱导的体内幼稚或记忆 CD8 T 细胞缺失的长期持续后果。我们的实验设计将使我们能够定义诱导和维持脓毒症诱导的 TRAIL 依赖性 T 细胞免疫抑制背后的细胞和分子机制。我们还期望从这些研究中获得的数据将有助于开发新的基于 TRAIL 的治疗方法，以抵消脓毒症引起的免疫抑制，这种抑制导致在这种不受控制的炎症反应期间出现大量死亡。