REGULATION OF IMMUNITY BY DEAD CELLS

死亡细胞对免疫的调节

基本信息

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
项目类别：
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

项目摘要

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.

抽象的死亡细胞对免疫系统的影响取决于细胞死亡的方式以及当前的免疫系统。人们的看法是，坏死细胞充当“危险”信号，而凋亡细胞则“沉默”。对于适应性免疫许多研究已经记录了坏死细胞的免疫原性活性，但现在已经很清楚了凋亡细胞可以引起非法的耐受反应。虽然很明显正常组织和淋巴细胞死亡可以诱导免疫耐受其他研究表明，在某些情况下，凋亡细胞可以具有免疫原性。了解这种动态取决于发现死亡细胞引发的因素调解这些影响。我们过去三年的研究已经建立了分子之间的联系细胞凋亡途径和免疫耐受过程。我们已经在一个系统中对此进行了探索，其中与经历凋亡的细胞残余物相关的抗原会抑制免疫反应。我们现在知道 caspase 激活、MOMP（线粒体外膜通透）和 ROS（反应性细胞凋亡过程中氧气的产生很重要。细胞凋亡过程中还会产生 ROS 修改危险信号 HMGB1（高迁移率族盒 1 蛋白），防止其免疫刺激影响。在本申请中，我们将进一步探讨 HMGB1 对诱导免疫耐受的影响凋亡细胞。我们提出 3 个目标：1）我们将定义 HMGB1 阻止耐受性的机制凋亡细胞； 2）我们将确定ROS修饰的HMGB1是否保留其促炎功能； 3）我们会确定其他细胞死亡途径是否通过修改危险信号来调节免疫反应活性氧生产。我们发现细胞凋亡过程中 ROS 的产生会改变危险信号 HMGB1 代表了危险信号生物学的重大范式转变。因此，HMGB1 的数量并不是可用，就是品质。我们进一步建议，并非所有 ROS 都有害，但可以提供保护对抗不需要的免疫反应。我们相信这些新原则广泛适用，并且这里提出的研究将进一步定义这些机制并确定是否存在模仿这些机制的潜力调节免疫反应的治疗方法的机制。