Regulation of Immunity by Dead Cells

描述（由申请人提供）：细胞凋亡在免疫系统中起着许多基本作用。这是胸腺自身反应性细胞被删除的过程（中央删除），它负责外周细胞的移除（外周删除）。细胞凋亡对于预防自身免疫和确保免疫特权部位的完整性具有重要意义。最近的研究描述了凋亡细胞的耐受性。我们的建议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。我们研究的基础将是Battisto和Bloom于1966年首次描述的具有良好特征的耐受系统。在这个系统中，静脉注射抗原偶联的脾细胞具有可重复性和强效的耐受性。这种方法已被证明对多种半抗原和抗原有效。最近，我们证明了该系统的耐受性是基于注射细胞的凋亡。然而，当使用活脾细胞时，凋亡是通过Fas/FasL途径介导的；细胞凋亡才是关键事件。本文提出的研究将采用一种独特的方法，通过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，来理解细胞凋亡在耐受性中的作用。我们拟开展以下研究：1)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，是耐受性的；3)我们将对凋亡细胞耐受的树突状细胞（DC）进行表征；4)我们将研究切断细胞凋亡到耐受通路的机制，并探讨其对免疫应答的影响。如果能准确地确定细胞凋亡的耐受性，就能更好地理解这个过程是如何帮助维持自我耐受性的。因此，这些研究可能会导致新的策略干预重要的临床问题，如移植排斥，自身免疫和肿瘤生物学。

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.