Roles of Dendritic Cells in Immune Regulation

描述（由申请人提供）：了解自身免疫中自身耐受性破坏的机制对于制定预防和治疗自身免疫疾病的策略至关重要。大量证据表明，免疫系统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不足以破坏免疫耐受，这表明其他细胞类型的凋亡受损在破坏自身耐受中起着至关重要的作用。靶向抑制树突状细胞（dc）凋亡已被证明可诱导全身自身免疫反应。为了验证树突状细胞凋亡在限制淋巴细胞活化和预防自身免疫中至关重要的假设，我们提出了以下实验目的：1)表征树突状细胞的凋亡途径。死亡受体介导的和线粒体依赖的凋亡途径将在dc中被表征。初步研究表明，体内DC亚群的寿命与抗凋亡和促凋亡bcl-2家族成员的分子比例有关。实验将进一步表征bcl-2调控的线粒体凋亡途径在调节DC细胞凋亡中的作用；2)验证dc细胞凋亡缺陷导致淋巴细胞活化失调的假说。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。在过度活化的淋巴细胞中检测细胞凋亡缺陷dc的可能性；3)验证dc细胞凋亡缺陷参与自身免疫发展的假说。研究将检验在线粒体凋亡途径中存在细胞凋亡缺陷的DCs是否会导致自身免疫的发展。我们提出了实验来验证细胞凋亡调节DC稳态和免疫原性的假设，以及DC细胞凋亡缺陷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用于开发更具体和有效的策略，通过靶向dc细胞凋亡来预防自身免疫的发生。

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.