APOPTOSIS OF ANTIGEN PRESENTING CELLS--ROLE IN AUTOIMMUNITY

抗原呈递细胞凋亡——在自身免疫中的作用

• 批准号: 5206190
• 负责人: DALIT ASHANY
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5206190
• 关键词: CD antigens; CD40 molecule; antigen presenting cell; apoptosis; autoimmunity; blocking antibody; cell adhesion molecules; cytokine; cytolysins; dendritic cells; helper T lymphocyte; immune tolerance /unresponsiveness; laboratory mouse; leukocyte adhesion molecules; ligands; macrophage; monoclonal antibody; pore forming protein; surface antigens; systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease, the etiology of which is unknown. Recently, three different lupus-prone mouse strains have been identified as having a genetic defect in a receptor ligand pair (Fas) which mediates apoptosis. These animal models emphasize the critical importance of lymphocyte apoptosis in maintaining self-nonself discrimination. The Fas apoptotic pathway has thus far been shown to have a significant role in maintaining peripheral tolerance of mature T and B cells. In contrast to data on lymphocytes, little is known about macrophage apoptosis. We have recently shown that activated macrophages presenting antigens are killed by antigen specific Th1 cells through the FasR. Our data suggest a novel mechanism by which FasR-FasL interactions may regulate immune responses at the level of the antigen presenting cell. We hypothesize that Th1 cell-mediated elimination of macrophages is required to maintain self tolerance and that failure to delete macrophages presenting self-peptide contributes to the expression of autoimmunity in Fas-deficient mice. The overall goal of our proposal is to study the functional significance of antigen-presenting cell (APC) apoptosis in normal immunoregulation and in SLE as well as to define which parameters (cytokines, activation and adhesion molecules) are required for Fas-mediated apoptosis of APCs. AIM 1 of this proposal will explore the roles of cytokines as well as macrophage cell surface activation and adhesion molecules in Fas mediated apoptosis. To study the selective effect of macrophage FasR deficiency in vivo (AIM 2), RAG-/MRL/lpr and RAG-/MRL/++ mice will be injected with MRL/++ lymphocytes depleted of macrophages and the onset and severity of autoimmunity compared. In AIM 3, we will examine the function of Fas on another potent APC, the dendritic cell. Our studies will explore further mechanism and functional significance of a novel immunoregulatory pathway between T cells and APCs and will expand our knowledge on the role of macrophages and dendritic cells in immunity and autoimmunity.

系统性红斑狼疮（SLE）是一种多器官自身免疫性疾病， 其病因尚不清楚。 最近，三种不同的狼疮倾向 小鼠品系已经被鉴定为具有遗传缺陷， 受体配体对（Fas）介导细胞凋亡。 这些动物模型 强调淋巴细胞凋亡在维持 自我与非自我的区别 迄今为止，Fas凋亡途径已被证明具有显著的 在维持成熟T和B细胞的外周耐受性中的作用。 在 与淋巴细胞的数据相反，对巨噬细胞的了解很少 凋亡 我们最近发现，活化的巨噬细胞呈现 抗原被抗原特异性Th 1细胞通过FasR杀死。 我们 数据提示了一种新的机制，通过这种机制，FasR-FasL相互作用可能 在抗原呈递细胞水平上调节免疫应答。 我们 假设需要Th 1细胞介导的巨噬细胞消除 维持自身耐受性以及未能删除巨噬细胞 提呈自身肽有助于表达自身免疫， Fas缺陷小鼠。 我们提案的总体目标是研究功能意义 抗原呈递细胞（APC）凋亡在正常免疫调节和 以及确定哪些参数（细胞因子、活化和 粘附分子）是Fas介导的APC凋亡所必需的。 目的 本提案的第一部分将探讨细胞因子的作用， Fas介导的巨噬细胞表面活化和粘附分子 凋亡 研究巨噬细胞Fas受体缺陷对人肝癌细胞的选择性作用， 体内（AIM 2）、RAG-/MRL/lpr和RAG-/MRL/++小鼠将注射 MRL/++淋巴细胞耗尽巨噬细胞和发病和严重程度 自身免疫性比较 在AIM 3中，我们将研究Fas在 另一种有效的APC，树突细胞。 我们的研究将进一步探讨其作用机制和功能意义 T细胞和APC之间的一种新的免疫调节途径， 我们对巨噬细胞和树突状细胞在免疫中的作用的认识 和自身免疫