Regulation of Immunity by Dead Cells

描述（由申请人提供）：细胞凋亡在免疫系统中发挥着许多基本作用。这是胸腺中自反应性细胞被删除（中央删除）的过程，并且负责外围细胞的删除（外围删除）。细胞凋亡对于预防自身免疫和确保免疫特权位点的完整性非常重要。最近的研究描述了凋亡细胞的耐受性。我们的提案将探讨细胞凋亡对耐受反应的几个方面，以确定细胞凋亡导致免疫耐受的原因。我们研究的基础是 Battisto 和 Bloom 于 1966 年首次描述的经过充分表征的耐受系统。在该系统中，静脉注射抗原偶联脾细胞可产生可重复且有效的耐受性。该方法已被证明对多种半抗原和抗原有效。最近我们证明该系统的耐受性是基于注射细胞的凋亡。然而，当使用存活的脾细胞时，细胞凋亡是通过 Fas/FasL 途径介导的；细胞凋亡才是关键事件。这里提出的研究将采用一种独特的方法来了解细胞凋亡在耐受中的作用，通过研究为什么细胞凋亡，特别是凋亡细胞，对正常生理学至关重要。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）我们将定义凋亡细胞本身的耐受性； 3) 我们将表征负责凋亡细胞耐受的树突状细胞 (DC)； 4）我们将研究一种将细胞凋亡消除为耐受途径的机制，并探讨其对免疫反应的影响。如果能够准确地确定细胞凋亡中的耐受原是什么，就能更好地理解这一过程如何帮助维持自我耐受。因此，这些研究可能会导致针对重要临床问题（例如移植物排斥、自身免疫和肿瘤生物学）的干预的新策略。

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.