REGULATION OF IMMUNITY BY DEAD CELLS

死亡细胞对免疫的调节

• 批准号: 8056821
• 负责人: Thomas Almon Ferguson
• 金额: $ 49.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056821
• 关键词: Antigens; Apoptosis; Apoptotic; Autoimmunity; Biology; Caspase; Cell Death; Cell Death Process; Cell Maturation; Cells; Cessation of life; Cytoplasmic Granules; DNA Damage; Dendritic Cells; Event; HMGB1 Protein; Health; Immune Tolerance; Immune response; Immune system; Immunity; Infection; Inflammation; Injury; Lead; Link; Lymphocyte; Mediating; Metabolic stress; Modeling; Modification; Molecular; Necrosis; Normal tissue morphology; Organ Transplantation; Outcome; Outer Mitochondrial Membrane; Oxidation-Reduction; Pathway interactions; Perception; Process; Production; Property; Reactive Oxygen Species; Regulation; Signal Transduction; System; Therapeutic; cytokine; cytotoxic; immunogenic; improved; oxidation; prevent; receptor; response; therapy development; tumor

DESCRIPTION (provided by applicant): The impact of dying cells on the immune system depends on the manner in which cells die, and the current perception is that necrotic cells act as "danger" signals while apoptotic cells are "silent". For adaptive immune responses, many studies have documented the immunogenic activity of necrotic cells, however it is now clear that apoptotic cells can illicit a tolerogenic response. While it is apparent that normal tissue and lymphocyte death can induce immune tolerance other studies have shown that in some cases apoptotic cells can be immunogenic. Understanding this dynamic depends on discovering the factors elicited by dying cells that mediate these effects. Our studies over the past 3 years have established a link between the molecular pathways of apoptosis and the process of immune tolerance. We have explored this in a system in which antigens associated with the remnants of cells undergoing apoptosis suppress the immune response. We now know that caspase activation, MOMP (mitochondrial outer membrane permeablization), and ROS (reactive oxygen species) production during apoptosis are important. Additionally ROS produced during apoptosis modifies the danger signal HMGB1 (for high mobility group box 1 protein) preventing its immunostimulatory effects. In this application we will further explore the effect of HMGB1 on the induction of immune tolerance by apoptotic cells. We propose 3 aims: 1) We will define the mechanism(s) by which HMGB1 blocks tolerance by apoptotic cells; 2) We will determine if ROS-modified HMGB1 retains its proinflammatory functions; 3) We will determine if other cell death pathways modulate the immune response by modifying danger signals through ROS production. Our finding that ROS production during apoptosis modifies the danger signal HMGB1 represents a major paradigm shift in the biology of danger signals. Thus, it is not the quantity of HMGB1 that is available, it is the quality. We would further suggest that not all ROS are harmful but may provide protection against unwanted immune responses. We believe that these new principles are wildly applicable and the studies proposed here will further define these mechanisms and determine if the potential exists to mimic those mechanisms in a therapeutic approach to modulating the immune response. PUBLIC HEALTH RELEVANCE: Our immune systems protect us from infection and other injuries. They can also turn against us and attack our own cells during organ transplantation and autoimmunity. The studies proposed here will improve our understanding of the immune system and lead to the development of therapies that can be use to control the immune response for our benefit.

描述（申请人提供）：死亡细胞对免疫系统的影响取决于细胞死亡的方式，目前的看法是坏死细胞充当“危险”信号，而凋亡细胞则“沉默”。对于适应性免疫反应，许多研究已经记录了坏死细胞的免疫原性活性，但现在清楚的是，凋亡细胞可以引发非法的耐受性反应。虽然正常组织和淋巴细胞死亡显然可以诱导免疫耐受，但其他研究表明，在某些情况下，凋亡细胞可能具有免疫原性。了解这种动态取决于发现介导这些效应的垂死细胞所引发的因素。我们过去三年的研究已经建立了细胞凋亡的分子途径和免疫耐受过程之间的联系。我们在一个系统中对此进行了探索，在该系统中，与经历凋亡的细胞残余物相关的抗原抑制免疫反应。我们现在知道，凋亡过程中 caspase 激活、MOMP（线粒体外膜通透）和 ROS（活性氧）产生非常重要。此外，细胞凋亡过程中产生的 ROS 会修改危险信号 HMGB1（高迁移率族蛋白 1），从而阻止其免疫刺激作用。在本申请中，我们将进一步探讨HMGB1对凋亡细胞诱导免疫耐受的影响。我们提出了 3 个目标：1）我们将定义 HMGB1 阻断凋亡细胞耐受的机制； 2）我们将确定ROS修饰的HMGB1是否保留其促炎功能； 3）我们将确定其他细胞死亡途径是否通过ROS产生改变危险信号来调节免疫反应。我们发现细胞凋亡过程中 ROS 的产生会改变危险信号 HMGB1，这代表了危险信号生物学的重大范式转变。因此，可用的 HMGB1 不是数量，而是质量。我们进一步建议，并非所有 ROS 都是有害的，但可以提供针对不需要的免疫反应的保护。我们相信这些新原理具有广泛的适用性，这里提出的研究将进一步定义这些机制，并确定是否存在在调节免疫反应的治疗方法中模拟这些机制的潜力。 公共卫生相关性：我们的免疫系统保护我们免受感染和其他伤害。它们还可以在器官移植和自身免疫过程中背叛我们并攻击我们自己的细胞。这里提出的研究将增进我们对免疫系统的了解，并导致开发可用于控制免疫反应以造福于我们的疗法。