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。这是一个自我反应细胞在胸腺中被删除（中央删除）的过程，它负责外周中的细胞清除（外周删除）。细胞凋亡对于防止自身免疫和确保免疫特权位点的完整性是重要的。最近的研究已经描述了凋亡细胞的致耐受性。我们的建议将探讨几个方面的凋亡耐受反应，以确定它是什么关于细胞凋亡，导致免疫耐受。我们研究的基础是Battisto和Bloom于1966年首次描述的良好表征的耐受系统。在该系统中，静脉注射抗原偶联的脾细胞产生了可重复的和有效的耐受性。该方法已被证明对广泛的半抗原和抗原有效。最近，我们证明，在这个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，细胞凋亡通过Fas/FasL途径介导;细胞凋亡是关键事件。这里提出的研究将采取一种独特的方法来理解细胞凋亡在耐受性中的作用，通过检查为什么细胞凋亡，特别是凋亡细胞，对正常生理学至关重要。本研究拟从以下几个方面进行研究：1）探讨FasL诱导的细胞死亡在耐受中的作用; 2）确定凋亡细胞本身是耐受原性细胞; 3）确定负责凋亡细胞耐受的树突状细胞（DC）的特征; 4）我们将研究消除细胞凋亡至耐受途径的机制，并探索免疫应答的后果。如果能够确切地确定什么是细胞凋亡耐受原，将更好地理解这一过程如何帮助维持自身耐受。因此，这些研究可能会导致重要的临床问题，如移植排斥，自身免疫和肿瘤生物学的干预新策略。

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.