Modulating Immunity through Dendritic Cell Phagocytic Receptors

通过树突状细胞吞噬受体调节免疫

• 批准号: 7527577
• 负责人: Nina Bhardwaj
• 金额: $ 42.35万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-23 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7527577
• 关键词: American College of Radiology; Animal Model; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Binding; CD8B1 gene; Cell Maturation; Cell physiology; Cells; Clinic; Cross Presentation; Cytosol; Dendritic Cells; Development; Disease; Event; Generations; Goals; Histones; Human; Immune System Diseases; Immunity; Immunotherapy; Individual; Integrins; Kidney; Laboratories; Lead; Learning; Lesion; Ligation; Macrophage-1 Antigen; Mediating; Modeling; Nature; Organ; Pathway interactions; Patients; Peripheral; Phagocytosis; Phagosomes; Physiological; Play; Prevention; Process; Property; Proteins; Public Health; Receptor Cell; Research Design; Role; Signal Pathway; Signal Transduction; Skin; Small Interfering RNA; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Tissues; Translating; anergy; base; design; imprint; in vivo; lymph nodes; migration; mouse model; novel; novel strategies; receptor; response

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are potent antigen presenting cells (APC) that play a central role in the induction of immunity and tolerance. In the steady state, DCs in peripheral tissues acquire self-antigens by phagocytosing neighboring cells that are undergoing apoptosis, as a result of physiologic cell turnover. Following migration to draining lymph nodes, DCs elicit self-antigen-specific, but tolerogenic responses from CD4+ and CD8+ T cells. Much remains to be learned about the events that distinguish the induction of tolerance vs. immunity during the cross-presentation of antigens derived from apoptotic cells (AC). For example, the hierarchy of AC receptors utilized by human DCs is unknown. We have shown that individual ligation of two such receptors, CR3 and CR4, inhibits human DC maturation, down modulates their immunostimulatory activity and leads to the abrogation of T cell responses. Therefore, by targeting CR3 and CR4 on DCs, AC can turn off self-reactive T- cell responses in the steady state. In this proposal, we plan to exploit AC receptors to induce tolerogenic human DCs. In the first aim we will assess the contribution of CR3 and CR4 towards TDC induction by using siRNA to block their expression in immature DC. Binding and phagocytosis of AC as well as immunostimulatory function will be evaluated. Secondly, we will identify the mechanism by which T cell tolerance is induced (deletion, anergy, and/or induction of regulatory T cells). In the second aim, we propose to identify relevant molecules and signaling pathways that lead to the induction of tolerogenic DCs (TDC). Advantage will be taken of the AC surrogate system to identify which signaling pathways are used by AC receptors on human DCs. The information gained will lead to a better understanding of TDC development and potentially, novel approaches for their generation ex vivo. The third aim will focus on developing animal models to test the tolerizing activity of AC receptor ligated DCs. We will (i) test whether CR3/4 ligated DCs induce tolerance to the model antigen OVA, and (ii) determine the nature of the tolerance induced (anergy, deletion and/or T regulatory cells). In the fourth aim, we will determine whether engagement of AC receptors on DC from patients with autoimmunity (Systemic Lupus Erythematosus) imparts them with tolerogenic properties. The goal is to take advantage of the selective effects of CR3/4 signaling to develop TDC with the capability of down-modulating autoimmune T cell responses. The information gained may lead to novel, physiologically relevant approaches that can be translated rapidly into the clinic to treat auto-immune disease. PUBLIC HEALTH RELEVANCE The prototypic autoimmune disease Systemic Lupus Erythematosus (SLE) is a multi-system disease manifested by lesions in the skin, kidney, and other organs. There remains no cure for the disease, which is considered to arise because of a prominent autoreactive response to self-antigens. The overall goal of this application is to develop physiologically relevant immunotherapies that can be used to treat SLE. The studies described will make use of novel approaches identified in our laboratory to suppress ongoing autoimmunity.

描述（由申请人提供）：树突状细胞（DC）是有效的抗原呈递细胞（APC），在诱导免疫和耐受性中发挥核心作用。在稳定状态下，外周组织中的 DC 通过吞噬由于生理细胞更新而正在发生凋亡的邻近细胞来获得自身抗原。迁移至引流淋巴结后，DC 会引发 CD4+ 和 CD8+ T 细胞的自身抗原特异性但耐受的反应。关于在凋亡细胞（AC）来源的抗原交叉呈递过程中区分耐受性诱导与免疫性诱导的事件还有很多有待了解。例如，人类 DC 使用的 AC 受体的层次结构是未知的。我们已经证明，单独连接两个此类受体 CR3 和 CR4 会抑制人类 DC 成熟，下调其免疫刺激活性并导致 T 细胞反应终止。因此，通过靶向 DC 上的 CR3 和 CR4，AC 可以关闭稳态下的自反应性 T 细胞反应。在本提案中，我们计划利用 AC 受体来诱导耐受性人类 DC。在第一个目标中，我们将通过使用 siRNA 阻断 CR3 和 CR4 在未成熟 DC 中的表达来评估 CR3 和 CR4 对 TDC 诱导的贡献。将评估 AC 的结合和吞噬作用以及免疫刺激功能。其次，我们将确定诱导 T 细胞耐受的机制（缺失、无反应性和/或诱导调节性 T 细胞）。在第二个目标中，我们建议鉴定导致耐受性树突状细胞（TDC）诱导的相关分子和信号通路。将利用 AC 替代系统来识别人类 DC 上的 AC 受体使用哪些信号传导途径。获得的信息将有助于更好地了解 TDC 的发展以及体外产生 TDC 的潜在新方法。第三个目标将侧重于开发动物模型来测试 AC 受体连接的 DC 的耐受活性。我们将 (i) 测试 CR3/4 连接的 DC 是否诱导对模型抗原 OVA 的耐受性，以及 (ii) 确定诱导的耐受性的性质（无反应性、缺失和/或 T 调节细胞）。在第四个目标中，我们将确定自身免疫性疾病（系统性红斑狼疮）患者的 DC 上的 AC 受体的结合是否赋予它们耐受性。目标是利用 CR3/4 信号传导的选择性效应来开发具有下调自身免疫 T 细胞反应能力的 TDC。获得的信息可能会带来新颖的、生理学相关的方法，这些方法可以迅速转化为临床治疗自身免疫性疾病。 公众健康相关性 典型自身免疫性疾病系统性红斑狼疮 (SLE) 是一种多系统疾病，表现为皮肤、肾脏和其他器官病变。这种疾病仍然无法治愈，被认为是由于对自身抗原的显着自身反应而引起的。该应用的总体目标是开发可用于治疗 SLE 的生理相关免疫疗法。所述研究将利用我们实验室发现的新方法来抑制持续的自身免疫。