Adaptive Immune Regulation of Traumatic Injury

创伤性损伤的适应性免疫调节

• 批准号: 10624318
• 负责人: JAMES A. LEDERER
• 金额: $ 41.46万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624318
• 关键词: Acute; Address; Affect; Antigens; Applied Research; Bacteria; Bacterial Pneumonia; Basic Science; Behavior; Biology; Burn Trauma; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical; Complex; Critical Illness; Data; Disease; Equilibrium; Goals; Health; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunology; Immunotherapy; Infection; Inflammation; Inflammatory; Injury; Knowledge; Life; Modeling; Molecular; Molecular Profiling; Mus; Nature; Opportunistic Infections; Organ; Outcome; Outcomes Research; Patients; Pattern; Peripheral; Persons; Phenotype; Predisposition; Process; Publishing; Reaction; Regulatory T-Lymphocyte; Reporting; Research; Series; Specificity; Stimulus; Systemic Inflammatory Response Syndrome; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Trauma; Traumatic injury; antimicrobial; cell type; cytokine; experimental study; immune function; immunoreaction; immunoregulation; improved; insight; interest; novel; post-trauma; response; restoration; severe injury; tissue injury

PROJECT SUMMARY Traumatic injuries disrupt immune system homeostasis, which can predispose patients to opportunistic infections and other trauma-associated complications like systemic inflammatory response syndrome (SIRS), organ damage, and chronic critical illnesses. Trauma induces unique and complex host responses that are initiated by tissue damage and the release of danger-associated molecular patterns (DAMPs) that trigger specific immune reactions. We identified that a subset of CD4+ T cells called regulatory T cells (Tregs) are acutely activated by injury in a mouse burn trauma model. The counter-inflammatory suppressive activity of Tregs is enhanced by trauma, which suggests that Tregs may control the intensity of post-trauma inflammation and restoration of immune system homeostasis. People can have different numbers of Tregs in their tissues or have different functional Treg responses to trauma that could determine trajectory of their response to traumatic injuries. Our hypothesis is that Tregs control immune reactions to DAMPs and influence the trajectory of the host response to trauma. To address this hypothesis, we propose a series of trauma immunology studies to systematically interrogate; 1) Treg control of immune system phenotypes and homeostasis, 2) trauma-induced Treg activation mechanisms, and 3) effects of modulating Tregs on immune phenotypes, anti-microbial immune function, and the two-hit SIRS response. The specific aims for this project are; 1) To determine how CD4+ Tregs control immune system reactivity to trauma, 2) To define the specificity and molecular nature of trauma-reactive CD4+ Tregs and other T cells, 3) To investigate how CD4+ Tregs influence anti-microbial immunity and two-hit SIRS. We anticipate that the outcome of this research will significantly advance our fundamental knowledge of specific immune mechanisms that modulate trauma immunity. We have several significant goals that we wish to achieve during the course of this project; 1) to provide new insights into the biology of Treg activation and function, 2) to develop a deeper understanding of immune system control of the mammalian trauma response, and 3) to explore the therapeutic potential of modulating Treg activation and function as a specific trauma immunotherapy to improve immune function and balance following trauma.

项目摘要 创伤性损伤破坏了免疫系统稳态，这可能使患者容易成为机会主义 感染和其他与创伤相关的并发症，例如全身性炎症综合征（SIRS）， 器官损伤和慢性重症疾病。创伤引起独特而复杂的宿主反应 通过组织损伤和触发危险相关的分子模式（潮湿）发起 特异性免疫反应。我们确定了一个CD4+ T细胞的子集称为调节T细胞（Treg）是 在小鼠烧伤创伤模型中急性激活。反炎症的抑制作用 Tregs通过创伤增强了，这表明Treg可以控制创伤后炎症的强度 并恢复免疫系统稳态。人们的组织中可以有不同数量的treg或 对创伤有不同的功能性Treg反应，这可以决定其对其对的反应的轨迹 创伤性伤害。我们的假设是Tregs控制了对潮湿的免疫反应，并影响 宿主对创伤的反应的轨迹。为了解决这一假设，我们提出了一系列创伤 免疫学研究系统询问； 1）Treg控制免疫系统表型和 稳态，2）创伤引起的Treg激活机制，3）调节Treg对免疫的影响 表型，抗微生物免疫功能和两次打击的SIRS反应。该项目的具体目的 是; 1）确定CD4+ Treg如何控制免疫系统对创伤的反应性，2）定义特异性 创伤反应性CD4+ Treg和其他T细胞的分子性质，3）研究CD4+ Treg如何 影响抗微生物免疫力和两次打击的SIRS。我们预计这项研究的结果将会 显着提高了我们对调节创伤的特定免疫机制的基本知识 免疫。在本项目过程中，我们希望实现几个重要的目标； 1）到 对Treg激活和功能的生物学提供新的见解，2）对 哺乳动物创伤反应的免疫系统控制，3）探索的治疗潜力 调节Treg激活和功能作为特定的创伤免疫疗法，以改善免疫功能和 创伤后的平衡。

项目成果

Distinct Injury Responsive Regulatory T Cells Identified by Multi-Dimensional Phenotyping.

• DOI: 10.3389/fimmu.2022.833100
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Multiplexed Plasma Immune Mediator Signatures Can Differentiate Sepsis From NonInfective SIRS: American Surgical Association 2020 Annual Meeting Paper.

• DOI: 10.1097/sla.0000000000004379
• 发表时间: 2020-10
• 期刊: Annals of surgery
• 影响因子: 9

Trauma induces expansion and activation of a memory-like Treg population.

• DOI: 10.1002/jlb.4a0520-122r
• 发表时间: 2021-03
• 期刊: JOURNAL OF LEUKOCYTE BIOLOGY
• 影响因子: 5.5
• 作者: Yamakawa, Kazuma;Tajima, Goro;Keegan, Joshua W.;Nakahori, Yasutaka;Guo, Fei;Seshadri, Anupamaa J.;Cahill, Laura A.;Lederer, James A.
• 通讯作者: Lederer, James A.