Targeting Trained Immunity in Trauma-Induced Immune Dysregulation

针对创伤引起的免疫失调中训练有素的免疫力

基本信息

批准号：
10714384
负责人：
JAMES A. LEDERER
金额：
$ 51.05万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-07 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714384
关键词：
Address Affect Agonist Bacterial DNA Binding Sites Biological Assay Blood Bone Marrow Bone Marrow Involvement Burn Trauma Burn injury Catalogs Cell Reprogramming Cells Chimera organism Critical Illness Cytometry DNA DNA Sequence Development Effector Cell Emergency Situation Epigenetic Process Eukaryotic Cell Flow Cytometry Gene Expression Profiling Genetic Transcription Granulopoiesis Hematopoietic Hematopoietic stem cells Histones Homeostasis Human Immune Immune response Immune system Immunity Immunologics Immunology Immunophenotyping Immunotherapeutic agent Immunotherapy In Vitro Infection Injury Life Lung Mediating Methodology Mitochondria Modeling Morbidity - disease rate Mus Operative Surgical Procedures Opportunistic Infections Peripheral Persons Phenotype Population Process Proteomics Proto-Oncogene Protein c-kit Radiation Injuries Reaction Recovery Regulator Genes Research Risk Role Signal Transduction Solid Sorting TLR9 gene Testing Therapeutic Intervention Time Training Translating Trauma Trauma patient Traumatic injury antimicrobial cell injury cytokine donor stem cell germ free condition hematopoietic stem cell differentiation hematopoietic stem cell niche immune health immune system function immunoregulation injured injury recovery insight medical countermeasure mesenchymal stromal cell mortality mouse model novel nuclease organ injury pre-clinical programs response targeted treatment therapeutic DNA trait transcription factor transcriptome sequencing treatment effect

项目摘要

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.

项目概要/摘要烧伤、爆炸或大手术造成的外伤会导致免疫系统功能失调，从而导致受伤者遭受危及生命的机会性感染或持续的危重疾病。用于恢复免疫系统功能和体内平衡的创伤性损伤尚未开发出来，人类的免疫表型多样性为进化目标提供了坚实的理由。保守的先天免疫调节网络对于治疗来说异质性较小。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有前途的靶向概念训练有素的免疫力可以降低创伤引起的并发症的发病率和死亡率。通过表观遗传改变免疫调节基因的可及性，发生在短命的先天免疫细胞中造血干细胞 (HSC)，然后通过分化传递给先天效应细胞，留下它们我们开发了 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 - 如促进辐射和创伤后免疫系统恢复的免疫治疗医学对策我们最近发现间充质基质细胞（MSC）是损伤中的关键细胞。骨髓造血干细胞 (HSC) 生态位，表达高 TLR9 水平，对 CpG-DNA 产生强烈反应刺激，并介导中性粒细胞减少小鼠感染的紧急粒细胞生成反应。促使我们将训练有素的免疫力视为有助于免疫保护的核心机制在此，我们提出以下假设：烧伤创伤和全身感染模型中的 CpG-DNA 治疗。 TLR9激动剂疗法介导保护性免疫并通过训练有素的免疫恢复免疫稳态为了检验这一假设，我们提出了以下具体的机制。目标：1) 描述 CpG-DNA 治疗创伤对造血和外周免疫的影响干预，2) 鉴定受损骨髓 MSC 和 HSC 的转录和表观遗传变化和用 CpG-DNA 处理的未受伤小鼠，以及 3) 生成并使用嵌合小鼠模型来描绘损伤和 CpG-DNA 诱导 HSC 转移的训练免疫表型。该研究项目将提供临床前机制见解，以将 CpG-DNA 转化为针对创伤引起的免疫失调的免疫治疗策略。