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，脓毒症患者的死亡通常不是由最初的脓毒症事件引起的，而是由随后的医院感染引起的。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，不仅存在消耗免疫系统的关键组分的淋巴细胞和骨髓细胞的显著凋亡，还存在剩余免疫细胞的功能降低。在动物和人类中的研究表明，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。使用盲肠结扎穿孔（CLP）模型诱导腹腔内腹膜炎，我们最近建立了脓毒症过程中产生的凋亡细胞和脓毒症诱导的免疫抑制的建立之间的机制联系。我们还发现脓毒症诱导的免疫抑制依赖于表达TNF相关的凋亡诱导配体（TRAIL）的CD 8 T细胞的产生。这些结果表明TRAIL在诱导脓毒症诱导的免疫抑制中起重要作用，并且我们使用这些信息来建立脓毒症的临床相关的“二次打击”模型，其更好地反映了脓毒症期间由于二次感染而观察到的延迟死亡率，以研究脓毒症诱导的免疫抑制的naove和记忆Ag特异性CD 8 T细胞对实验性二次细菌感染的应答。 我们提出的实验将研究脓毒症（CLP治疗）小鼠不能清除继发性感染的假设，因为T细胞区室的全身抑制，部分是由TRAIL依赖性机制介导的。因此，将评价以下不同但互补的具体目标：1 -分析脓毒症后对继发感染的原代CD 8 T细胞应答并确定TRAIL在脓毒症诱导的免疫抑制中的作用，2 -确定脓毒症影响预先存在的记忆CD 8 T细胞的功能的程度并研究TRAIL在该过程中的作用，和3 -确定体内脓毒症诱导的新生或记忆CD 8 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确定脓毒症诱导的TRAIL依赖性T细胞免疫抑制的诱导和维持背后的细胞和分子机制。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TRAIL的治疗方法，用于抵消脓毒症诱导的免疫抑制，该免疫抑制导致在这种不受控制的炎症反应期间观察到的大量死亡。

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.