Enhancing Innate and Adaptive Immunity to Improve Sepsis Survival

项目摘要/摘要 脓毒症被定义为由于危及生命而发生的一种失调的宿主炎症反应 感染时存在器官功能障碍。败血症是大多数人最常见的死亡原因 每年在美国造成超过25万人死亡。这个 由于人口老龄化和相关的免疫力减弱，脓毒症的发病率正在增加。 发生在老年人身上的制度。直到最近，大多数关于脓毒症的研究都集中在阻断最初的 高炎性细胞因子介导的疾病阶段。改进的治疗方案导致了 大多数患者在脓毒症的最初高炎性阶段存活下来，并进入旷日持久的 免疫抑制阶段。脓毒症中的大多数死亡发生在免疫抑制阶段 无序。脓毒症免疫抑制阶段的死亡通常是由于未能控制原发感染。 感染或继发性医院获得性感染的结果，通常带有机会性病原体 从而突显出东道主的免疫力受损。多种潜伏病毒的重新激活，包括 迁延性脓毒症患者中出现的巨细胞病毒和单纯疱疹病毒进一步证明了 这些患者的免疫抑制程度很深。在动物身上有越来越多的证据 研究以及来自小型II期临床试验的数据表明，提高宿主免疫力的治疗方法 该系统可改善脓毒症的发病率和死亡率。这种基于免疫治疗的方法对脓毒症有 在过去的十年里一直是首席调查员关注的焦点。目前的提案是这些方案的延伸 调查。 这项提案的首要目标是确定新的免疫辅助疗法，以恢复宿主 免疫，减少病原体负担，改善器官损伤，提高脓毒症的存活率。我们正在集中精力 测试具有良好安全性并正在进行临床试验的免疫调节剂。只是 就像一个精心调整的管弦乐队一样，当免疫系统的所有不同组件都 和谐地工作。脓毒症导致宿主免疫的多种缺陷，很可能是这种组合 免疫疗法可能为脓毒症提供最好的保护。因此，这项研究的第二个主要目标是测试 针对脓毒症所致先天免疫和获得性免疫缺陷的联合免疫治疗 它们被认为在损害宿主免疫力方面发挥着关键作用。顺利完成这项研究 将使新发现的药物能够快速转化为脓毒症的临床试验，并提供一条新的前进道路 对抗这种迄今难以治愈的疾病。

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.