Dysfunctional Myelopoiesis and Myeloid-Derived Suppressor Cells in Sepsis Pathobiology

摘要 更早地认识到脓毒症和改进最佳做法的实施大大减少了住院时间 过去十年的死亡率。随着住院存活率的提高，没有完全康复的患者数量 恢复率大幅增加；近50%的外科脓毒症患者永远不会完全恢复，近 其中三分之一的患者将在6个月内死亡。目前，一个困扰医学界的重要关键问题 实践者的问题是：为什么一些外科脓毒症患者恢复得很快，而另一些人的长期结果却很差 尽管我们尽了最大的努力？为什么我们的一些疾病(如癌症、终末期肾病等)会并存？ 面临无法恢复风险增加的人口？我们最重要的假设是， 外科脓毒症(死亡和生活质量差)是宿主白细胞异位症不能解决的结果， 类似于其他慢性疾病，如癌症和自身免疫性疾病。具体地说， 髓系来源的抑制细胞(MDSCs)的优先扩增和自我永生化 部分通过骨髓(BM)祖细胞和MDSCs的表观遗传学变化，推动非急性 脓毒症后感染性和非感染性并发症。该计划将研究人类外科手术 脓毒症是导致“功能失调的骨髓生成”、骨髓间充质干细胞数量扩张、 T细胞数量/功能受抑与患者免疫抑制/炎症的发展 内型。我们将主要关注外科脓毒症患者的MDSC扩张是如何随着时间的推移而演变的 骨髓生成是如何在转录和表观遗传学上被调控的？ 创伤患者的骨髓是发生脓毒症的高危人群。它有四个具体目标：目标1.测试 急性外科败血症后宿主MDSCs持续存在的假说导致较差的长期临床疗效 外科败血症的结果，包括但不限于继发性感染的增加。目标2.测试 外科脓毒症未能康复的假说是由循环中可修改的表观遗传学改变所致 诱导和延长免疫抑制内型的MDSCs。目标3.识别不同的 外科脓毒症患者MDSCs随时间的免疫抑制机制包括 免疫代谢，检查点抑制，活性氧和氮的产生，以及底物的可用性。 目的4.检验这一假设，即对最初的炎症刺激的反应，发展的风险增加 外科脓毒症继发于优先骨髓造血干细胞驱动的免疫抑制 MDSCs在转录和表观遗传学上的细胞(HSC)扩增。这将在严重钝性创伤中进行分析。 创伤后脓毒症的高危患者，早期表现为骨髓祖细胞和扩增 免疫抑制的骨髓间充质干细胞。利用已建立的脓毒症和危重病的临床基础设施 研究中心(SCIRC)，将采用团队科学的方法，与来自 多个临床和基础科学学科。目前正在举行的定期双周会议讨论方案问题， 资源和专业发展，以及时间和精力的分配和冲突的解决。

ABSTRACT Earlier recognition of sepsis and improved implementation of best practices have significantly reduced in-hospital mortality over the past decade. As in-hospital survival has improved, the number of patients who do not fully recover has dramatically increased; nearly 50% of surgical sepsis patients will never fully recover and nearly one-third of these patients will die within 6 months. Currently, one important critical question that vexes medical practitioners is: why do some surgical sepsis patients rapidly recover while others have poor long-term outcomes despite our best supportive efforts? Why are some of our comorbid (i.e. cancer, end-stage renal disease, etc.) populations at increased risk of nonrecovery? Our overarching hypothesis is that the consequences of surgical sepsis (death and poor quality of life) are the result of an unresolving host leukocyte dyscrasia, similar to other chronic conditions such as cancer and autoimmune disease. Specifically, the preferential expansion and self-perpetuation of myeloid-derived suppressor cells (MDSCs), propagated in part through epigenetic changes in both bone marrow (BM) progenitors and MDSCs, drives non-acute infectious and noninfectious complications after sepsis. This Program will investigate in human surgical sepsis the underlying mechanisms that drive ‘dysfunctional myelopoiesis’, expansion of MDSC populations, suppressed T-cell quantities/function, and the development of patient’s immunosuppressive/inflammatory endotypes. We will primarily focus on how MDSC expansion evolves over time in surgical sepsis patients who do or do not rapidly recover; how myelopoiesis is regulated transcriptionally and epigenetically in the bone marrow of trauma patients who are at high risk of developing sepsis. There are four specific aims: Aim 1. To test the hypothesis that perpetuation of host MDSCs after acute surgical sepsis drives poor long-term clinical outcomes in surgical sepsis, including but not limited to increased secondary infections. Aim 2. To test the hypothesis that failure to recover from surgical sepsis is driven by modifiable epigenetic alterations in circulating MDSCs that induce and prolong immunosuppressive endotypes. Aim 3. To identify the distinct immunosuppressive mechanisms of MDSCs from surgical sepsis patients over time, including immunometabolism, check-point inhibition, reactive oxygen and nitrogen production, and substrate availability. Aim 4. To test the hypothesis that in response to an initial inflammatory stimulus, the increased risk of developing surgical sepsis is secondary to immunosuppression driven by a preferential bone marrow hematopoietic stem cell (HSC) expansion of MDSCs transcriptionally and epigenetically. This will be analyzed in severe blunt trauma patients at high risk for post-injury sepsis who manifest early changes in bone marrow progenitors and expansion of immunosuppressive MDSCs. Using the established clinical infrastructure of the Sepsis and Critical Illness Research Center (SCIRC), a team science approach will be employed with collaborating PI’s coming from multiple clinical and basic science disciplines. Ongoing regular biweekly meetings currently address program, resource and professional development, as well as time and effort allocation and conflict resolution.