APOPTOSIS OF ANTIGEN PRESENTING CELLS--AUTOIMMUNITY ROLE

我对自身免疫性疾病及其发病机制产生了兴趣， 全身性风湿病，通过我的临床训练和 我在免疫学研究中获得的经验。我的切身利益 是细胞凋亡和免疫调节。拟议项目将加强 我的研究技能，并将应用最先进的技术， 理解细胞凋亡和T细胞抗原作用的方法 提呈细胞（APC）在系统性自身免疫中的相互作用。这 经验将使我能够实现我的长期目标， 独立调查员埃尔康博士的实验室在 该项目所需的大多数技术，并取得了重大进展 在细胞凋亡和小鼠狼疮模型领域的贡献。的 特殊外科医院的科学环境和 康奈尔大学医学中心提供直接访问一个优秀的 多机构免疫学计划，并允许密切合作 调查人员精通多个相关领域。 这 环境提供了实现目标的最佳环境。 本提案的总体目标是研究 APC凋亡在正常免疫调节和系统性免疫损伤中意义 红斑狼疮以及确定哪些参数（细胞因子， 活化和粘附分子）是Fas介导的 APCs的凋亡。本提案的目标1将探讨以下方面的作用： 细胞因子以及巨噬细胞表面活化和粘附 Fas介导的凋亡。为了研究 体内巨噬细胞Fas受体缺陷（Aim 2）、RAG/MRL/pr和RAG/MRL/++ 小鼠将注射耗尽巨噬细胞的MRL/++淋巴细胞， 自身免疫的发作和严重程度进行比较。在目标3中，我们 检测Fas在树突状细胞中的功能。在目标4中，我们将 本研究对正常人和病人的单核细胞和巨噬细胞进行了研究， 关于SLE 我们的研究将进一步探讨其作用机制和功能 T细胞与APCs之间一种新免疫调节途径及其意义 并将扩大我们对巨噬细胞和树突状细胞作用的认识， 细胞免疫和自身免疫。

I have developed my interest in autoimmunity and the pathogenesis of systemic rheumatiC disease both through my clinical training and the experience I have gained in immunology research. My immediate interest is in apoptosis and immune regulation. The proposed project will enhance my research skills and will apply state of the art techniques and approaches toward understanding the role of apoptosis and T cell:antigen presenting cell (APC) interactions in systemic autoimmunity. This experience will enable me to attain my long-term goal of becoming an independent investigator. Dr. Elkon's laboratory has expertise in the majority of techniques needed for this project and has made significant contribution's in the fields of apoptosis and murine lupus models. The scientific environment of the Hospital for Special Surgery and the Cornell University Medical Center provides direct access to an excellent multi-institutional immunology program and allows close collaborations with investigators expert in a multitude of related fields. This environment provides the optimal situation in which to achieve my goals. The overall goal of the current proposal is to study the functional significance of APC apoptosis in normal immunoregulation and in systemic lupus erythematosus 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/pr 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 in dendritic cells. In Aim 4 we will extend our study to human monocytes and macrophages from normals and patients with SLE. Our studies will explore further the 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.