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: 8097582
• 负责人: Nina Bhardwaj
• 金额: $ 41.53万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097582
• 关键词: 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; MAPK3 gene; Macrophage-1 Antigen; Mediating; Modeling; Nature; Organ; Pathway interactions; Patients; Peripheral; Phagocytosis; Phagosomes; Physiological; Play; Prevention; Process; Property; Proteins; Receptor Cell; Regulatory T-Lymphocyte; Research Design; Role; Signal Pathway; Signal Transduction; Skin; Small Interfering RNA; System; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; Testing; Tissues; Translating; anergy; base; design; imprint; in vivo; lymph nodes; migration; mouse model; novel; novel strategies; public health relevance; 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发挥核心作用。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来获得自身抗原，这是生理性细胞更新的结果。在迁移到引流淋巴结后，DC从CD 4+和CD 8 + T细胞引发自身抗原特异性但致耐受性应答。关于在来自凋亡细胞（AC）的抗原的交叉呈递期间区分耐受性与免疫性的诱导的事件，仍有许多有待了解。例如，人DC利用的AC受体的层次是未知的。我们已经表明，单独连接两个这样的受体，CR 3和CR 4，抑制人DC成熟，下调其免疫刺激活性，并导致废除T细胞反应。因此，通过靶向DC上的CR 3和CR 4，AC可以关闭稳态下的自身反应性T细胞应答。在这个提议中，我们计划利用AC受体来诱导致耐受性人DC。在第一个目标中，我们将通过使用siRNA阻断它们在未成熟DC中的表达来评估CR 3和CR 4对TDC诱导的贡献。将评价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，我们提出鉴定导致诱导致耐受性DC（TDC）的相关分子和信号通路。将利用AC替代系统来鉴定人DC上的AC受体使用哪些信号传导途径。所获得的信息将导致更好地了解TDC的发展和潜在的，新的方法，为他们的代离体。第三个目标将集中于建立动物模型以测试AC受体连接的DC的耐受活性。我们将（i）测试CR 3/4连接的DC是否诱导对模型抗原OVA的耐受，和（ii）确定诱导的耐受的性质（无反应性、缺失和/或T调节细胞）。在第四个目标中，我们将确定是否参与AC受体对DC的患者自身免疫性（系统性红斑狼疮）赋予他们的耐受性。目标是利用CR 3/4信号传导的选择性作用来开发具有下调自身免疫T细胞应答的能力的TDC。所获得的信息可能会导致新的，生理相关的方法，可以迅速转化为临床治疗自身免疫性疾病。 系统性红斑狼疮（SLE）是一种多系统疾病，表现为皮肤、肾脏和其他器官的病变。目前还没有治愈这种疾病的方法，这种疾病被认为是由于对自身抗原的显著自身反应性反应而引起的。本申请的总体目标是开发可用于治疗SLE的生理学相关免疫疗法。所描述的研究将利用我们实验室确定的新方法来抑制正在进行的自身免疫。

项目成果

Modulation of human Th17 cell responses through complement receptor 3 (CD11 b/CD18) ligation on monocyte-derived dendritic cells.

通过补体受体3（CD11b/CD18）结扎对单核细胞衍生的树突状细胞的补体3（CD11b/CD18）的调节。

• DOI: 10.1016/j.jaut.2018.05.005
• 发表时间: 2018-08
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Nowatzky J;Manches O;Khan SA;Godefroy E;Bhardwaj N
• 通讯作者: Bhardwaj N

Matrix metalloproteinase-2 conditions human dendritic cells to prime inflammatory T(H)2 cells via an IL-12- and OX40L-dependent pathway.

• DOI: 10.1016/j.ccr.2011.01.037
• 发表时间: 2011-03-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Godefroy E;Manches O;Dréno B;Hochman T;Rolnitzky L;Labarrière N;Guilloux Y;Goldberg J;Jotereau F;Bhardwaj N
• 通讯作者: Bhardwaj N