A Novel Inflammatory Dendritic Cell in Lupus Nephritis

狼疮性肾炎中的一种新型炎症树突状细胞

基本信息

批准号：
10475392
负责人：
Latha Prabha Ganesan
金额：
$ 10万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475392
关键词：
Adoptive Transfer Affect Attenuated Autoimmune Diseases Autoimmunity Biological Response Modifiers Biology CD14 gene CD3 Antigens CD34 gene Cells Chronic Complication Consequentialism Data Dendritic Cells Dendritic cell activation Development Disease FCGR3B gene Feedback Flare Genetic Transcription Health Helper-Inducer T-Lymphocyte Hematopoietic stem cells Heterogeneity Histologic Human IL3RA gene ITGAM gene ITGAX gene IgG Receptors Immune Immune response Immunologics In Situ In Vitro Infiltration Inflammation Inflammatory Injury Injury to Kidney Investigation Kidney Knowledge Lead Lupus Lupus Nephritis Mediating Methods Modeling Morbidity - disease rate Mus Organ Outcome Pathogenesis Pathogenicity Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Phenotype Play Population Proteins Role Synapses Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Time Toxic effect Transcript Work cell type cost cytokine disorder control improved improved outcome in vivo insight kidney biopsy new therapeutic target novel novel therapeutics overexpression polarized cell prevent public health relevance renal damage side effect tissue injury transcriptomics

项目摘要

Title: A Novel Inflammatory Dendritic Cell in Lupus Nephritis Abstract/Project Summary: Dendritic cells (DC) are important immune regulators that play a pivotal role in autoimmunity by either promoting tolerance or promoting self-reactive immune responses. Accordingly, aberrant activation of DC is implicated in the pathogenesis of most autoimmune diseases. We have identified a new subset of inflammatory dendritic cells (infDC) that are found in abundance in the kidneys of patients with lupus nephritis (LN), the most common serious organ complication of systemic lupus erythematosus (SLE). These infDC are localized mainly to the periglomerular region of human LN kidney during active disease, a compartment of the kidney not well studied in LN. Of particular relevance is that is that in human LN kidneys infDC appear to spatially associate with T cells that transcriptionally resemble Th17 cells. This is significant because of the known relevance of Th17 pathways in LN. Taken together we suggest that the periglomerular co-localization of infDC and Th17 cells are consequential in initiating and exacerbating LN. The central hypothesis of this proposal is that infDC are the master initiators and drivers of local inflammatory kidney injury by activation of Th17 cells during LN, and that characterizing these relationships will improve our understanding of LN pathogenesis and lead to new therapeutic opportunities. This hypothesis will be tested in three aims. In Aim 1, periglomerular infDC and T cell expression patterns will be characterized in human LN to determine expression heterogeneity and correlation with disease activity. The second aim tests the hypothesis that infDC are damaging to the kidney during LN by demonstrating that depleting or increasing infDC attenuates or exacerbates intra-renal inflammation during LN. The third aim will test the hypothesis that infDC initiate an inflammatory pathway by supporting a cytokine milieu that differentiates intra-renal naïve T cells to a Th17 phenotype. This proposal is significant as it will establish the mechanisms by which this novel population of InfDC initiates and maintains tissue injury during LN flare, and in turn will identify the relevant inflammatory pathways that can be targeted to attenuate flare and improve outcomes in LN. In summary, this work should provide new insights into how renal inflammation is initiated during LN flare by describing how periglomerular InfDC drive the local immune response in the kidney. Thus our investigations are expected to yield a major advance in understanding the basic biology behind kidney-specific autoimmunity during human LN.

标题：狼疮性肾炎中的一种新型炎症树突状细胞摘要/项目摘要：树突状细胞（DC）是重要的免疫调节剂，通过以下任一方式在自身免疫中发挥关键作用：促进耐受或促进自身反应性免疫反应因此，DC 的异常激活是。我们已经确定了一个新的自身免疫性疾病的发病机制。狼疮性肾炎患者肾脏中大量存在炎症树突状细胞 (infDC) (LN)，系统性红斑狼疮 (SLE) 最常见的严重器官并发症，这些 infDC 是。在活动性疾病期间，主要定位于人类 LN 肾的肾小球周围区域，肾脏在 LN 中尚未得到充分研究。特别相关的是，在人类 LN 肾脏中，infDC 似乎与转录上类似于 Th17 细胞的 T 细胞在空间上相关，这一点很重要，因为 Th17 通路在 LN 中的已知相关性综上所述，我们认为肾小球周围共定位。 infDC 和 Th17 细胞的数量对于引发和加剧 LN 至关重要。建议认为，infDC 是局部炎症性肾损伤的主要引发者和驱动因素，通过激活 LN 期间的 Th17 细胞，表征这些关系将提高我们对 LN 的理解该假设将在三个目标中得到检验。将在人 LN 中表征肾小球周围 infDC 和 T 细胞表达模式以确定表达第二个目标检验 infDC 的假设。通过证明减少或增加 infDC 会减弱或增加 LN 期间对肾脏的损害第三个目标将检验 infDC 引发肾内炎症的假设。通过支持将肾内幼稚 T 细胞分化为 Th17 的细胞因子环境来调节炎症通路该提案意义重大，因为它将建立这一新群体的机制。 InfDC 在 LN 发作期间启动并维持组织损伤，进而识别相关炎症可针对减轻 LN 耀斑和改善预后的途径。总之，这项工作应该为 LN 发作期间肾脏炎症如何引发提供新的见解。描述肾小球周围的 InfDC 如何驱动肾脏的局部免疫反应，从而我们的研究。预计将在理解肾脏特异性自身免疫背后的基础生物学方面取得重大进展在人类 LN 期间。