Roles of Dendritic Cells in Immune Regulation

描述(由申请人提供)：了解自身免疫中自我耐受性崩溃的机制对于制定预防和治疗自身免疫性疾病的策略至关重要。大量证据表明，免疫系统中的细胞凋亡缺陷与人类和小鼠全身性自身免疫性疾病的发生有关。然而，仅抑制淋巴细胞的凋亡并不足以打破免疫耐受，这表明其他类型细胞的凋亡受损在自我耐受的破坏中起着关键作用。靶向抑制树突状细胞(DC)的凋亡可诱导全身自身免疫反应。为了验证DC中的凋亡对于限制淋巴细胞活化和防止自身免疫是必不可少的这一假说，我们提出了以下特定目的的实验：1)研究DC中的凋亡途径。死亡受体介导的和线粒体依赖的凋亡通路将是DC的特征。初步研究表明，体内DC亚群的寿命与抗凋亡和促凋亡bcl2家族成员的分子比例有关。实验将进一步表征bcl2调控的线粒体凋亡通路在调控DC凋亡中的作用；2)验证DC凋亡缺陷导致淋巴细胞激活失调的假说。树突状细胞的寿命可以通过影响树突状细胞刺激淋巴细胞的持续时间来潜在地影响免疫反应。本课程将探讨过度活化的淋巴细胞中的凋亡缺陷树突状细胞的潜能；以及3)检验树突状细胞凋亡缺陷有助于自身免疫发展的假说。研究将探讨线粒体凋亡途径中存在凋亡缺陷的DC是否会导致自身免疫的发生。实验被用来验证这样的假设，即细胞凋亡调节DC的动态平衡和免疫原性，而DC中有缺陷的细胞凋亡有助于自身免疫的发生。从长远来看，从这些研究中获得的知识将被用来开发更具体和有效的策略，通过靶向DC的凋亡来防止自身免疫的发生。

DESCRIPTION (provided by applicant): Understanding the mechanisms for the breakdown of self-tolerance in autoimmunity is essential for the development of strategies to prevent and treat autoimmune diseases. Abundant evidence has shown that defective apoptosis in the immune system is associated with the development of systemic autoimmune diseases in humans and mice. However, inhibition of apoptosis in lymphocytes alone is not sufficient to break immune tolerance, indicating that impaired apoptosis in other cell types plays a critical role in the breakdown of self-tolerance. Targeted inhibition of apoptosis in dendritic cells (DCs) has been shown to induce systemic autoimmune responses. Experiments are proposed to test the hypothesis that apoptosis in DCs is essential for limiting lymphocyte activation and preventing autoimmunity in the following specific aims: 1) to characterize the apoptosis pathways in DCs. Death receptor-mediated and mitochondrion-dependent apoptosis pathways will be characterized in DCs. Preliminary studies suggested that the lifespan of DC subsets in vivo was correlating to the molecular ratios between anti-apoptotic and pro-apoptotic bcl-2 family members. Experiments will be performed to further characterize the bcl-2-regulated mitochondrial apoptosis pathways in regulating DC apoptosis; 2) to test the hypothesis that defective apoptosis in DCs contributes to dysregulated lymphocyte activation. The lifespan of DCs can potentially influence immune responses by affecting the duration of DCs in stimulating lymphocytes. The potentials for apoptosis-deficient DCs in over- activating lymphocytes will be examined; and 3) to test the hypothesis that defective apoptosis in DCs contributes to the development of autoimmunity. Studies will be performed to examine whether DCs harboring apoptosis deficiency in the mitochondrial apoptosis pathways leads to the development of autoimmunity. Experiments are proposed to test the hypothesis that apoptosis regulates DC homeostasis and immunogenicity, and defective apoptosis in DCs contributes to the onset of autoimmunity. In the long term, the knowledge gained from these studies will be used to develop more specific and effective strategies to prevent the onset of autoimmunity by targeting apoptosis in DCs.