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的稳态，这可能使患者容易发生机会性免疫缺陷。 感染和其他创伤相关并发症，如全身炎症反应综合征（SIRS）， 器官损伤和慢性危重病。创伤诱导独特而复杂的宿主反应， 由组织损伤和释放引发炎症的炎症相关分子模式（DAMP）引发 特异性免疫反应。我们发现，一个称为调节性T细胞（Treg）的CD 4 + T细胞亚群， 在小鼠烧伤创伤模型中被损伤急性激活。抗炎抑制活性的 创伤可增强TdR，这表明TdR可能控制创伤后炎症的强度 和恢复免疫系统的稳态。人们的组织中可能有不同数量的TbR， 对创伤有不同的功能性Treg反应，这可以决定他们对创伤反应的轨迹， 外伤我们的假设是，TdR控制对DAMP的免疫反应，并影响免疫应答。 宿主对创伤的反应轨迹为了解决这个假设，我们提出了一系列的创伤 免疫学研究以系统地询问; 1）免疫系统表型的Treg控制， 体内平衡，2）创伤诱导的Treg活化机制，和3）调节Treg对免疫调节的作用。 表型、抗微生物免疫功能和两次打击SIRS反应。本项目的具体目标 1）为了确定CD 4 + T细胞如何控制免疫系统对创伤的反应性，2）为了确定CD 4 + T细胞的特异性， 创伤反应性CD 4 + T细胞和其他T细胞的分子性质，3）为了研究CD 4 + T细胞在创伤中的作用， 影响抗微生物免疫和二次感染SIRS。我们预计，这项研究的结果将 显著地推进了我们对调节创伤特异性免疫机制的基础知识 免疫力我们有几个重要的目标，我们希望在这个项目的过程中实现：1） 为Treg激活和功能的生物学提供新的见解，2）更深入地了解 哺乳动物创伤反应的免疫系统控制，以及3）探索 调节Treg活化和功能作为特异性创伤免疫疗法以改善免疫功能， 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.

多路复用血浆免疫介质特征可以将败血症与非感染的SIRS区分开：美国手术协会2020年会议论文。

• 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.