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（由申请人提供）：垂死细胞对免疫系统的影响取决于细胞死亡的方式，而当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，但是现在很明显，凋亡细胞可以非法产生耐受性反应。显然，正常组织和淋巴细胞死亡可以诱导免疫耐受性，其他研究表明，在某些情况下，凋亡细胞可能是免疫原性的。理解这种动态取决于发现通过介导这些作用的垂死细胞引起的因素。在过去的三年中，我们的研究建立了凋亡的分子途径与免疫耐受性过程之间的联系。我们已经在一个系统中探讨了这一点，在该系统中，与经历凋亡的细胞残留物相关的抗原抑制了免疫反应。我们现在知道，凋亡过程中的胱天蛋白酶激活，MOMP（线粒体外膜透化）和ROS（活性氧）的产生很重要。另外，在凋亡期间产生的ROS会改变危险信号HMGB1（对于高迁移率组1蛋白），以防止其免疫刺激作用。在此应用中，我们将进一步探讨HMGB1对凋亡细胞诱导免疫耐受性的影响。我们提出3个目标：1）我们将定义HMGB1阻止凋亡细胞耐受性的机制； 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通过ROS生产来修饰危险信号来调节免疫反应。我们的发现，凋亡过程中的ROS产生改变了危险信号HMGB1代表危险信号生物学的主要范式转移。因此，可用的不是HMGB1的数量，而是质量。我们进一步建议，并非所有ROS都是有害的，但可以提供防止不必要的免疫反应的保护。我们认为，这些新原则非常适用，此处提出的研究将进一步定义这些机制，并确定是否存在以一种调节免疫反应的治疗方法模仿这些机制的潜力。 公共卫生相关性：我们的免疫系统可保护我们免受感染和其他伤害。在器官移植和自身免疫期间，他们还可以反对我们并攻击我们自己的细胞。这里提出的研究将提高我们对免疫系统的理解，并导致可以用于控制免疫反应以供利益的疗法的发展。