Regulation of Immunity by Dead Cells

死亡细胞对免疫的调节

• 批准号: 7409557
• 负责人: Thomas Almon Ferguson
• 金额: $ 36.4万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409557
• 关键词: Affect; Antigens; Apoptosis; Apoptosis Inhibitor; Apoptotic; Autoimmunity; CD8-Positive T-Lymphocytes; Cell Death; Cell Line; Cell Maturation; Cells; Cellular Immunity; Cessation of life; Clinical; Contact hypersensitivity; Cross-Priming; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Ensure; Event; Excision; Experimental Autoimmune Encephalomyelitis; Gene Targeting; Generations; Graft Rejection; Haptens; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Induction of Apoptosis; Injection of therapeutic agent; Intervention; Knowledge; Lead; Literature; Mediating; Methods; Modeling; Mus; Nature; Necrosis; Numbers; Outcome; Pathway interactions; Peripheral; Personal Satisfaction; Phenotype; Physiology; Play; Population; Principal Investigator; Process; Property; Proteins; Range; Regulation; Role; Self Tolerance; Signal Transduction; Site; Splenocyte; System; T-Cell Proliferation; T-Lymphocyte; Thymus Gland; Tolerogen; Tumor Biology; base; in vivo; intravenous injection; novel; prevent; programs; response

DESCRIPTION (provided by applicant): Apoptosis plays a number of fundamental roles in the immune system. It is the process by which self reactive cells are deleted in the thymus (central deletion) and it is responsible for cell removal in the periphery (peripheral deletion). Apoptosis is important for preventing autoimmunity and ensuring the integrity of immune privileged sites. Recent studies have described the tolerogenic nature of apoptotic cells. Our proposal will explore several aspects of the apoptosis to tolerance response to determine what it is about apoptosis that leads to immune tolerance. The basis for our studies will be the well characterized tolerance system first described in 1966 by Battisto and Bloom. In this system intravenous injection of antigen-coupled splenocytes gave reproducible and potent tolerance. This method has proven effective for a wide range of haptens and antigens. Recently we demonstrated that tolerance in this system was based on apoptosis of the injected cells. Apoptosis was mediated via the Fas/FasL pathway when viable splenocytes are used however; it was apoptosis that was the key event. The studies proposed here will take a unique approach to understanding the role of apoptosis in tolerance by examining why apoptosis, and specifically apoptotic cells, are critical for normal physiology. We propose to study the following: 1) We will explore the role of FasL induced cell death in tolerance; 2) we will define what it is about the apoptotic cell, per se, that is tolerogenic; 3) we will characterize the dendritic cell (DC) responsible for tolerance by apoptotic cells; 4) we will investigate a mechanism to ablate the apoptosis to tolerance pathway and explore the consequences for the immune response. If it can be determined exactly what it is about apoptosis that is tolerogen, a better understanding of how this process helps maintain self tolerance will be gained. Consequently, these studies may lead to new strategies of intervention in important clinical problems such as graft rejection, autoimmunity and tumor biology.

描述（由申请人提供）：凋亡在免疫系统中起许多基本作用。这是在胸腺中删除自反应性细胞的过程（中央缺失），并导致外周中的细胞去除（外围缺失）。凋亡对于防止自身免疫和确保免疫特权部位的完整性很重要。最近的研究描述了凋亡细胞的耐受性。我们的建议将探索凋亡的几个方面，以确定导致免疫耐受性的凋亡的阳性反应。我们研究的基础将是Battisto和Bloom在1966年首次描述的宽容系统。在该系统中，抗原耦合的脾细胞的静脉注射可重现和有效的耐受性。该方法已被证明对多种触觉和抗原有效。最近，我们证明了该系统中的耐受性是基于注射细胞的凋亡。但是，当使用活脾细胞时，通过FAS/FASL途径介导凋亡。凋亡是关键事件。这里提出的研究将采用一种独特的方法来通过研究为什么凋亡，特别是凋亡细胞对正常生理至关重要的原因，以理解凋亡在耐受性中的作用。我们建议研究以下内容：1）我们将探讨FASL诱导的细胞死亡在耐受性中的作用； 2）我们将定义对凋亡细胞的含有耐受性的凋亡细胞； 3）我们将表征负责凋亡细胞耐受性的树突状细胞（DC）； 4）我们将研究一种消除凋亡以耐受性途径的机制，并探讨免疫反应的后果。如果可以准确地确定阳离子的凋亡是什么，那么将获得对该过程如何帮助维持自耐受的更好的理解。因此，这些研究可能导致在重要的临床问题（例如移植物排斥，自身免疫和肿瘤生物学）中采取新的干预策略。