Regulation of Immunity by Dead Cells

描述(由申请人提供)：细胞凋亡在免疫系统中扮演着许多基本的角色。它是胸腺中自身反应性细胞被删除的过程(中央删除)，并负责外围细胞的删除(外围删除)。细胞凋亡对于防止自身免疫和确保免疫特权部位的完整性具有重要意义。最近的研究已经描述了凋亡细胞的耐受性。我们的提案将探讨细胞凋亡耐受反应的几个方面，以确定导致免疫耐受的细胞凋亡是什么。我们研究的基础将是1966年由拜蒂斯托和布鲁姆首次描述的具有良好特性的容忍系统。在该系统中，静脉注射抗原偶联的脾细胞可获得重复性和强大的耐受性。这种方法已被证明对广泛的半抗原和抗原有效。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。然而，当使用活的脾细胞时，细胞凋亡是通过Fas/FasL途径介导的；凋亡是关键事件。这里提出的研究将采取一种独特的方法来了解细胞凋亡在耐受中的作用，研究为什么细胞凋亡，特别是凋亡细胞，对正常生理至关重要。我们打算进行以下研究：1)我们将探索FasL诱导的细胞死亡在耐受中的作用；2)我们将定义什么是凋亡细胞本身，即耐受；3)我们将通过凋亡细胞来表征负责耐受的树突状细胞(DC)；4)我们将研究一种机制，以消除凋亡到耐受的途径，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是耐受原是什么，就会更好地理解这一过程如何帮助维持自身耐受。因此，这些研究可能导致在移植排斥、自身免疫和肿瘤生物学等重要临床问题上采取新的干预策略。

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.