Targeting Trained Immunity in Trauma-Induced Immune Dysregulation

项目摘要/摘要 烧伤、爆炸或大手术造成的创伤性损伤会导致免疫系统功能失调，从而导致 伤者到危及生命的机会性感染或持续性危重疾病。靶向免疫疗法 对于创伤损伤来说，恢复免疫系统功能和动态平衡的作用尚未开发出来，而且正在 急需之物。人类免疫表型的多样性为进化靶点提供了坚实的理由 保守的天然免疫调节网络，用于治疗的异质性较低。因此， 通过一种称为“训练免疫”的过程对先天免疫细胞进行重新编程是一个很有前途的靶向概念。 减少创伤并发症的发病率和死亡率的治疗方法。训练有素的免疫力可以 发生在短暂的先天免疫细胞中，通过表观遗传改变免疫调节基因的可及性 造血干细胞(HSC)，然后通过分化传递给先天效应细胞，留下它们 更好地准备好应对感染。我们已经开发出Toll样受体9(TLR9)激动剂-未甲基化 Cpg-DNA序列，天然存在于细菌DNA和真核细胞线粒体中-AS 促进辐射和创伤后免疫系统恢复的免疫治疗医学对策 受伤。我们最近发现，间充质基质细胞(MSCs)是体内重要的细胞驻留细胞 骨髓造血干细胞(HSC)定位，表达高水平的TLR9，与CpG-DNA强烈反应 刺激和介导中性粒细胞减少症小鼠对感染的紧急粒系反应。这一发现 促使我们认为训练有素的免疫力是促进免疫保护的核心机制 烧伤创伤和感染模型中的系统CpG-DNA治疗。在这里，我们解决的假设是 TLR9激动剂治疗通过训练免疫介导保护性免疫和恢复免疫动态平衡 涉及骨髓间充质干细胞和造血干细胞的机制。为了验证这一假设，我们提出了以下具体建议 目的：1)用CpG-DNA治疗来描述创伤的造血和外周免疫后果 干预，2)鉴定损伤的骨髓间充质干细胞和造血干细胞的转录和表观遗传学变化 和未损伤的CpG-DNA处理的小鼠，以及3)建立并使用嵌合小鼠模型来描绘 损伤和CpG-DNA诱导HSCs转移的训练性免疫表型。我们预计结果会是 这一研究计划将为将CpG-DNA翻译为 创伤性免疫失调的免疫治疗策略。

PROJECT SUMMARY/ABSTRACT Traumatic injuries from burns, blasts, or major surgery dysregulates immune system function predisposing the injured people to life-threatening opportunistic infections or persistent critical illness. Targeted immunotherapies for traumatic injuries to restore immune system function and homeostasis have not yet been developed and are urgently needed. The immunophenotypic diversity in humans provides a solid justification to target evolutionarily conserved innate immunoregulatory networks that are less heterogenous for treatment. As such, the reprogramming of innate immune cells by a process called “trained immunity” is a promising concept for targeting therapeutics to reduce the morbidity and mortality from trauma-induced complications. Trained immunity can occur in short-lived innate immune cells by epigenetically modifying accessibility to immune regulatory genes in hematopoietic stem cells (HSC), which are then passed on by differentiation to innate effector cells, leaving them better poised to respond to infection. We have developed Toll-like receptor 9 (TLR9) agonists – unmethylated CpG-DNA sequences, which are naturally found in bacterial DNA and eukaryotic cell mitochondria - as immunotherapeutic medical countermeasures to promote immune system recovery after radiation and traumatic injuries. We recently discovered that mesenchymal stromal cells (MSCs), which are critical cellular residents in the bone marrow hematopoietic stem cell (HSC) niche, express high TLR9 levels, strongly react to CpG-DNA stimulation, and mediate emergency granulopoiesis responses to infection in neutropenic mice. This discovery prompted us to consider trained immunity as a central mechanism contributing to the immune protection from systemic CpG-DNA treatment in our burn trauma and infection model. Here, we address the hypothesis that TLR9 agonist therapy mediates protective immunity and restores immune homeostasis by trained immunity mechanisms involving bone marrow MSCs and HSCs. To test this hypothesis, we propose the following specific aims: 1) To delineate hematopoietic and peripheral immune consequences of trauma with CpG-DNA therapeutic intervention, 2) To identify transcriptional and epigenetic changes in bone marrow MSCs and HSCs from injured and uninjured mice treated with CpG-DNA, and 3) To generate and use chimeric mouse models to delineate injury and CpG-DNA induced trained immunity phenotypes transferred by HSCs. We anticipate that the results from this research program will provide pre-clinical mechanistic insights towards translating CpG-DNA as an immunotherapeutic strategy for trauma-induced immune dysregulation.