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），在诱导免疫和耐受中起核心作用。在稳定状态下，外周组织中的dc通过吞噬正在经历凋亡的邻近细胞获得自身抗原，这是生理性细胞周转的结果。在迁移到引流淋巴结后，dc会引起CD4+和CD8+ T细胞的自身抗原特异性耐受性反应。在交叉呈递来自凋亡细胞（AC）的抗原时，区分耐受性诱导与免疫诱导的事件仍有待了解。例如，人类dc所利用的AC受体的层次结构是未知的。我们已经证明，单独连接两个这样的受体CR3和CR4，抑制人类DC成熟，下调其免疫刺激活性，并导致T细胞反应的消除。因此，通过靶向dc上的CR3和CR4， AC可以在稳态下关闭自反应性T细胞反应。在本研究中，我们计划利用交流受体诱导耐受性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。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（删除、激活和/或诱导调节性T细胞）。在第二个目标中，我们提出确定导致耐受性dc （TDC）诱导的相关分子和信号通路。将利用AC替代系统的优势来确定人类dc上的AC受体使用哪些信号通路。所获得的信息将有助于更好地理解TDC的发展，并可能为它们的体外生成提供新的方法。第三个目标将集中在开发动物模型来测试AC受体连接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）确定诱导耐受性的性质（能量、缺失和/或T调节细胞）。在第四个目标中，我们将确定AC受体对自身免疫（系统性红斑狼疮）患者DC的作用是否赋予其耐受性。目的是利用CR3/4信号的选择性作用，开发具有下调自身免疫T细胞反应能力的TDC。获得的信息可能会导致新的，生理学相关的方法，可以迅速转化为临床治疗自身免疫性疾病。