Suppression of T cell immunity during sepsis

描述(由申请人提供)： 脓毒症是大多数重症监护病房的主要死亡原因，败血症患者的死亡通常不是由最初的败血症事件引起的，而是由随后的医院感染引起的。在严重脓毒症中幸存下来的患者通常表现出严重的免疫功能受损。在脓毒症期间，不仅淋巴和髓系细胞发生显著的凋亡，耗尽免疫系统的关键成分，而且剩余的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是导致脓毒症发病和随后死亡的关键因素。利用盲肠结扎和穿孔(CLP)模型诱导腹内腹膜炎，我们最近建立了脓毒症时产生的细胞凋亡和脓毒症诱导的免疫抑制之间的机制联系。我们还发现，脓毒症诱导的免疫抑制依赖于表达肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的CD8T细胞的产生。这些结果表明TRAIL在脓毒症诱导的免疫抑制中起着重要作用，我们利用这些信息建立了一个临床相关的二次击打脓毒症模型，该模型更好地反映了二次感染导致的脓毒症延迟死亡，以研究脓毒症诱导的NAOVE和记忆性抗原特异性CD8 T细胞对实验性继发性细菌感染的免疫抑制反应。我们提议的实验将调查这样的假设，即脓毒症(CLP治疗)小鼠无法清除继发感染，因为T细胞隔间的系统性抑制，这部分是由TRAIL依赖的机制介导的。因此，将评估以下不同但互补的特定目标：1-分析脓毒症后原代CD8 T细胞对继发感染的反应，并确定TRAIL在脓毒症诱导的免疫抑制中的作用；2-确定脓毒症对原有记忆CD8 T细胞功能的影响程度并研究TRAIL在这一过程中的作用；3-确定脓毒症导致体内NAOVE或记忆性CD8 T细胞缺失的长期后果。我们的实验设计将使我们能够确定脓毒症诱导和维持TRAIL依赖性抑制T细胞免疫的诱导和维持背后的细胞和分子机制(S)。我们还预计，我们从这些研究中获得的数据将有助于开发基于TRAIL的新治疗方法，以对抗脓毒症诱导的免疫抑制，这种免疫抑制导致在这种不可控的炎症反应中出现大量死亡。

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.