Enhancing Innate and Adaptive Immunity to Improve Sepsis Survival

项目总结/摘要 脓毒症被定义为由于危及生命的炎症反应而发生的失调的宿主炎症反应。 感染并伴有器官功能障碍。脓毒症是大多数人死亡的最常见原因。 重症监护室，每年造成美国超过25万人死亡。的 由于人口老龄化和相关的免疫功能减弱，脓毒症的发病率正在增加。 发生在老年人身上的系统。直到最近，大多数关于脓毒症的研究都集中在阻断最初的 过度炎症性的尼古丁介导的疾病阶段。改进的治疗方案导致 大多数患者在脓毒症的初始高炎症阶段存活下来，并进入长期的 免疫抑制期败血症中的大多数死亡发生在免疫抑制阶段， disorder.在脓毒症的免疫抑制阶段死亡通常是由于未能控制原发性免疫缺陷。 感染或继发性医院获得性感染的结果，通常伴有机会性病原体 从而凸显宿主免疫力受损多种潜伏病毒的重新激活， 巨细胞病毒和单纯疱疹病毒在长期脓毒症患者中的发生进一步证明了 这些患者的免疫抑制程度很深。越来越多的证据表明， 研究以及来自小型II期临床试验的数据表明，增强宿主免疫的疗法 系统可以改善脓毒症的发病率和死亡率。这种基于免疫治疗的脓毒症治疗方法 在过去的十年里一直是首席研究员的焦点。目前的建议是这些建议的延伸。 调查事务所 该提案的总体目标是确定新的免疫辅助疗法， 免疫、降低病原体负荷、改善器官损伤和提高脓毒症患者存活率。我们专注 在测试免疫调节剂，具有良好的安全性，并在目前的临床试验。只是 就像一个微调的管弦乐队，免疫系统的功能最有效时，其所有的各种组成部分， 和谐地工作。脓毒症诱导宿主免疫的多种缺陷， 免疫疗法可能为脓毒症提供最佳保护。因此，本研究的第二个主要目标是测试 针对特异性脓毒症诱导的先天性和适应性免疫缺陷的联合免疫疗法 其被认为在损害宿主免疫力中起关键作用。本研究的成功完成 将使新发现的药物能够快速转化为脓毒症的临床试验，并提供新的前进方向。 对抗这种迄今为止难以治愈的疾病

Project Summary/Abstract Sepsis is defined as a dysregulated host inflammatory response that occurs due to life-threatening infection with the presence of organ dysfunction. Sepsis is the most frequent cause of mortality in most intensive care units and is responsible for over a quarter million deaths in the United States annually. The incidence of sepsis is increasing because of the aging population and the associated weakening of the immune system that occurs in the aged. Until recently, most research on sepsis was focused on blocking the initial hyper-inflammatory cytokine-mediated phase of the disorder. Improved treatment protocols have resulted in most patients surviving this initial hyper-inflammatory phase of sepsis and entering a protracted immunosuppressive phase. The majority of deaths in sepsis occur during this immunosuppressive phase of the disorder. Deaths in this immunosuppressive phase of sepsis are typically due to failure to control the primary infection or a result of acquisition of secondary hospital-acquired infections, often with opportunistic pathogens thereby underscoring the host’s impaired immunity. The reactivation of multiple latent viruses including cytomegalovirus and herpes simplex virus that occurs in patients with protracted sepsis further attests to the profound degree of immunosuppression in these patients. There is a growing body of evidence in animal studies as well as data from small phase II clinical trials indicating that therapies which boost the host immune system can improve morbidity and mortality in sepsis. This immuno-therapeutic based approach to sepsis has been the focus of the principal investigator for the last decade. The current proposal is an extension of these investigations. The overarching goal of this proposal is to identify new immuno-adjuvant therapies that restore host immunity, decrease pathogen burden, ameliorate organ injury, and improve survival in sepsis. We are focusing on testing immune modulatory agents that have an excellent safety profile and are in current clinical trials. Just like a finely-tuned orchestra, the immune system functions most effectively when all its various components are working harmoniously. Sepsis induces multiple defects in host immunity and it is likely that combination immunotherapy may offer the best protection in sepsis. Thus, a second major goal of this study is to test combination immunotherapy targeted against specific sepsis-induced defects in innate and adaptive immunity which are believed to play a critical role in compromising host immunity. Successful completion of this study would enable rapid translation of newly identified drugs into clinical trials in sepsis and offer a new way forward against this heretofore intractable disease.