Adaptive Immune Regulation of Traumatic Injury

创伤性损伤的适应性免疫调节

基本信息

批准号：
10186694
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
项目类别：
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/10186694
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 Phenotype Process Publishing Regulatory T-Lymphocyte Reporting Research Series Specificity Stimulus Systemic Inflammatory Response Syndrome T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Trauma Traumatic injury antimicrobial base cell type cytokine experimental study immune function immunoreaction immunoregulation improved injured insight interest novel post-trauma response restoration severe injury tissue injury

项目摘要

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.

项目概要创伤性损伤会破坏免疫系统的稳态，使患者容易出现机会性感染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疾病。创伤会引起独特而复杂的宿主反应由组织损伤和危险相关分子模式 (DAMP) 的释放引发特异性免疫反应。我们发现 CD4+ T 细胞的一个子集称为调节性 T 细胞 (Treg) 在小鼠烧伤模型中因损伤而急性激活。抗炎抑制活性 Tregs 因创伤而增强，这表明 Tregs 可能控制创伤后炎症的强度和恢复免疫系统稳态。人们的组织中可能有不同数量的 Tregs，或者对创伤有不同的功能性 Treg 反应，这可以决定他们对创伤的反应轨迹外伤。我们的假设是 Tregs 控制对 DAMP 的免疫反应并影响宿主对创伤反应的轨迹。为了解决这个假设，我们提出了一系列的创伤系统地进行免疫学研究； 1) Treg控制免疫系统表型和稳态，2) 创伤诱导的 Treg 激活机制，以及 3) 调节 Tregs 对免疫的影响表型、抗微生物免疫功能和两次打击 SIRS 反应。该项目的具体目标是; 1) 确定 CD4+ Tregs 如何控制免疫系统对创伤的反应，2) 定义特异性以及创伤反应性 CD4+ Tregs 和其他 T 细胞的分子性质，3) 研究 CD4+ Tregs 是如何影响抗微生物免疫力和二次打击 SIRS。我们预计这项研究的结果将显着提高我们对调节创伤的特定免疫机制的基础知识免疫。我们希望在该项目过程中实现几个重要目标； 1) 到提供对 Treg 激活和功能生物学的新见解，2) 加深对免疫系统控制哺乳动物的创伤反应，3) 探索治疗潜力调节 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。