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)：濒临死亡的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，坏死细胞扮演着“危险”信号的角色，而凋亡细胞则处于“沉默”状态。对于获得性免疫反应，许多研究已经证明了坏死细胞的免疫原性，然而现在清楚的是，凋亡细胞可以破坏耐受性反应。虽然很明显，正常组织和淋巴细胞的死亡可以诱导免疫耐受，但其他研究表明，在某些情况下，凋亡的细胞可以产生免疫原性。理解这一动态依赖于发现由死亡细胞引发的因素，这些因素介导了这些影响。我们在过去三年的研究已经建立了细胞凋亡的分子途径与免疫耐受过程之间的联系。我们在一个系统中探索了这一点，在这个系统中，与细胞凋亡残留物相关的抗原抑制了免疫反应。我们现在知道，caspase的激活、线粒体外膜通透性(MOMP)和活性氧(ROS)的产生在细胞凋亡过程中是重要的。此外，细胞凋亡过程中产生的ROS修饰危险信号HMGB1(高迁移率族蛋白1)，阻止其免疫刺激作用。在这一应用中，我们将进一步探讨HMGB1在凋亡细胞诱导免疫耐受中的作用。我们提出了三个目标：1)我们将确定HMGB1阻断凋亡细胞耐受的机制(S)；2)我们将确定ROS修饰的HMGB1是否保留了其促炎功能；3)我们将确定其他细胞死亡途径是否通过产生ROS来改变危险信号来调节免疫反应。我们的发现是，在细胞凋亡过程中ROS的产生修改了危险信号HMGB1，这代表了危险信号生物学中的一个重大范式转变。因此，HMGB1的可获得性不是数量的问题，而是质量的问题。我们进一步认为，并不是所有的ROS都是有害的，但可能会提供保护，防止不必要的免疫反应。我们相信这些新的原则是广泛适用的，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仿这些机制的可能性。与公共健康相关：我们的免疫系统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，它们也可以转而反对我们，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，并导致可用于控制免疫反应的治疗方法的开发，使我们受益。