A Novel Immune Stimulatory Ligand in Autoimmunity-Associated Angiogenesis

自身免疫相关血管生成中的新型免疫刺激配体

• 批准号: 8699012
• 负责人: Joseph Holoshitz
• 金额: $ 34.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699012
• 关键词: Accounting; Affinity; Amino Acid Sequence; Angiogenic Factor; Autoimmune Process; Autoimmunity; Blood Vessels; Cell surface; Cells; Code; Collagen Arthritis; Data; Dendritic Cells; Disease; Endothelial Cells; Enhancers; Epitopes; Event; Goals; HLA-DRB1; IL8 gene; Immune; In Vitro; Interleukin-17; Interleukin-6; Knowledge; Laboratory Study; Ligands; Mediating; Molecular; Monocyte Chemoattractant Protein-1; Mus; Natural Immunity; Nitric Oxide; Patients; Play; Process; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Role; Signal Transduction; Synovial Membrane; T-Lymphocyte; angiogenesis; antiangiogenesis therapy; base; calreticulin; cellular transduction; design; improved; in vitro Model; in vivo; inhibitor/antagonist; mouse model; novel; novel therapeutics; receptor; treatment strategy

DESCRIPTION (provided by applicant): The "shared epitope" (SE) - a HLA-DRB1-encoded 5-amino acid sequence motif carried by the vast majority of rheumatoid arthritis (RA) patients - is associated with severe disease. The mechanistic basis of RA-SE association is unknown. In prior studies, this laboratory has demonstrated that the SE acts as a signal transduction ligand that activates nitric oxide (NO) production in other cells. SE signaling is transduced by cell surface calreticulin (CRT), a known innate immunity receptor previously implicated in immune regulation, autoimmunity and angiogenesis. To better understand the pathogenic role of the SE in RA, we have begun characterizing SE signaling events in RA-related cells. Preliminary data demonstrate that in dendritic cells (DCs) the SE is a potent inhibitor of regulatory T (Treg) cells and enhancer of pro-angiogenic, IL-17- producing T (Th17) cells. In endothelial cells (ECs), the SE triggers production of the pro-angiogenic factors, IL-8, IL-6 and monocyte chemotactic protein-1 (MCP-1). Additionally, it was found the CRT is over- citrullinated in the synovium of RA patients and citrullinated CRT showed markedly higher affinity to the SE and transduced much more potent signals than the unmodified protein. Thus, the SE triggers angiogenesis- relevant functional events that could account for its effect in RA. The main goal of the research proposed here is to characterize the effect of the SE in angiogenesis, a key pathgenetic mechanism in several autoimmune conditions, including RA. Specifically, we propose to: 1. Characterize the functional effect of SE-mediated Th17 polarization using mouse models of tolerance and collagen-induced arthritis (CIA); 2. Determine the effect of the SE-CRT on EC activation in experimental mouse models of angiogenesis and CIA; 3. Determine the role of CRT citrullination in SE-activated pro- angiogenic effect in mouse ECs Collectively, these studies offer an examination of a novel paradigm that provides a unifying explanation for several important mechanistic aspects of RA. In the long run, the new knowledge gained in this project could provide a basis for designing novel therapeutic strategies.

描述（由申请人提供）：“共享表位”（SE） - 绝大多数类风湿关节炎（RA）患者携带的HLA-DRB1编码的5-氨基酸序列基序与严重疾病有关。 RA-SE关联的机械基础尚不清楚。在先前的研究中，该实验室表明SE充当信号转导配体，该配体激活其他细胞中一氧化氮（NO）的产生。 SE信号传导被细胞表面钙网蛋白（CRT）转导，这是一种先前与免疫调节，自身免疫和血管生成有关的已知先天免疫受体。为了更好地了解SE在RA中的致病作用，我们已经开始表征与RA相关细胞中SE信号事件的表征。初步数据表明，在树突状细胞（DCS）中，SE是调节性T（Treg）细胞的有效抑制剂和促血管生成的增强子IL-17-产生T（Th17）细胞。在内皮细胞（EC）中，SE触发了促血管生成因子的产生，即IL-8，IL-6和单核细胞趋化蛋白1（MCP-1）。此外，发现CRT在RA患者的滑膜中被过度cILTRULLALLED，而Citrulladined CRT对SE的亲和力明显更高，并且与未修饰的蛋白质相比，传递了更有效的信号。因此，SE会触发血管生成 - 相关的功能事件，可以解释其在RA中的影响。这里提出的研究的主要目标是表征SE在血管生成中的影响，这是在包括RA在内的几种自身免疫性条件下的关键途径机制。具体而言，我们提出：1。使用耐受性的小鼠模型和胶原蛋白诱导的关节炎（CIA）来表征SE介导的Th17极化的功能效应； 2。确定SE-CRT对血管生成和CIA的实验小鼠模型中EC激活的影响； 3。确定CRT柠檬酸在统称小鼠EC中的SE激活性血管生成作用中的作用，这些研究提供了对新型范式的研究，该研究为RA的几个重要机械方面提供了统一的解释。从长远来看，该项目中获得的新知识可以为设计新颖的治疗策略提供基础。