REGULATION OF IMMUNITY BY DEAD CELLS

死亡细胞对免疫的调节

• 批准号: 8244504
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244504
• 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; 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; abstracting; cytokine; cytotoxic; immunogenic; improved; oxidation; prevent; receptor; response; therapy development; tumor

Abstract 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.

摘要