Role of Siglec-E in Regulating Alloimmunity

Siglec-E 在调节同种免疫中的作用

• 批准号: 10392512
• 负责人: Leonardo V. Riella
• 金额: $ 41.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392512
• 关键词: Acute; Address; Adoptive Cell Transfers; Agonist; Allografting; Antigen Presentation; Binding; Biological Response Modifiers; Biology; CD86 gene; Cell Maturation; Cells; Clinic; Computer Models; Confocal Microscopy; Data; Dendritic Cells; Dendritic cell activation; Disease; Dose; Down-Regulation; Drug usage; Family; Flow Cytometry; Generations; Graft Survival; Heart; Heart Transplantation; Human; Immune; Immune response; Immune system; Immunoglobulins; Immunologic Receptors; Immunoprecipitation; Immunosuppression; Immunosuppressive Agents; In Situ; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Kidney Transplantation; Lead; Lectin; Ligands; Lung; Mus; Natural Immunity; Organ Survival; Organ Transplantation; PTPN11 gene; Pathway interactions; Peptides; Pharmaceutical Preparations; Process; Property; Proteins; Regulatory T-Lymphocyte; Role; Sialic Acids; Signal Pathway; Signal Transduction; Skin Transplantation; Skin graft; Solid; Stains; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Transplant Recipients; Transplantation; Transplantation Tolerance; Ubiquitination; Western Blotting; Work; adaptive immunity; antigen processing; antigen-specific T cells; base; design; effective therapy; effector T cell; humanized mouse; immune activation; immunoregulation; improved; in vivo; innovation; insight; isoimmunity; mycobacterial; novel; novel therapeutics; organ transplant rejection; prevent; receptor; response; screening; sialic acid binding Ig-like lectin; side effect; simulation; skin allograft; small molecule; synthetic peptide; therapeutic target; transplant model; ubiquitin ligase

Abstract Despite the significant improvements in short-term survival of organ transplants, rejection remains a leading cause of long-term transplant loss. Innate immune activation potentiates the adaptive immunity and is a crucial player in precipitating acute rejection and preventing transplant tolerance. However, most immunosuppressive drugs used in the clinic primarily target T cells and not innate immune cells. Therefore, there is an unmet need to develop effective therapies to modulate innate immunity in transplantation. Siglec (sialic acid-binding immunoglobulin-like lectin)-E, or SigE, is an innate receptor that down-modulates inflammation. SigE is expressed by dendritic cells (DCs) and inhibits TLRs-triggered inflammatory responses. Engagement of SigE is a promising strategy to promote immune regulation. However, the role of SigE in transplantation has not been investigated. We have found that allografts lacking SigE have an accelerated rejection, and kidney transplant patients have decreased expression of human SigE counterpart (Siglec-9) during rejection. Moreover, we have recently discovered that a mycobacterial protein DnaK can bind to SigE with potent immunomodulatory effects in alloimmunity by decreasing DCs activation through downregulation of MHC II and CD86. In situ targeting of donor DCs with DnaK is capable of prolonging skin allograft survival in the absence of systemic immunosuppression and DnaK-effect was dependent on SigE. Thus, targeting SigE represents a novel potential therapeutic target to enhance the modulation of the immune response in transplantation. Based on our preliminary data, we hypothesize that SigE is a critical regulator of the immune response following transplantation. To address this hypothesis, we propose three specific aims: 1) To define the role of SigE in regulating DC maturation and antigen processing; 2) To determine the role of SigE in alloimmunity and in the generation of antigen-specific T cells; and 3) To investigate a novel immunomodulatory molecule designed based on the interaction between Siglec-9 and DnaK. To accomplish these aims, we will utilize heart and humanized mouse transplantation models, a novel synthetic agonist peptide to SigE, SigE-deficient mice, tracking of antigen-specific T cells using adoptive transferred cells and endogenous staining using tetramers. The proposed studies are innovative and significant because we will explore the biology of an important regulatory innate immune receptor, SigE, in transplantation and we will investigate a novel SigE targeting molecule to inhibit alloimmunity,

抽象的 尽管器官移植的短期存活率显着提高，但排斥反应仍然是导致器官移植失败的主要原因。 长期移植失败。先天免疫激活增强了适应性免疫，并且在免疫系统中发挥着重要作用。 诱发急性排斥反应并防止移植耐受。然而，大多数免疫抑制药物用于 该诊所主要针对 T 细胞，而不是先天免疫细胞。因此，开发有效的解决方案的需求尚未得到满足。 调节移植中先天免疫的疗法。 Siglec（唾液酸结合免疫球蛋白样凝集素）-E，或 SigE 是一种下调炎症的先天受体。 SigE 由树突状细胞 (DC) 表达并抑制 TLRs 触发炎症反应。 SigE 的参与是促进免疫调节的一种有前景的策略。 然而，SigE 在移植中的作用尚未得到研究。我们发现同种异体移植物缺乏SigE 排斥反应加速，肾移植患者的人类 SigE 对应物表达减少 (Siglec-9) 拒绝期间。此外，我们最近发现分枝杆菌蛋白 DnaK 可以结合 SigE 在同种免疫中具有有效的免疫调节作用，通过下调 MHC II 和 CD86。用 DnaK 原位靶向供体 DC 能够延长皮肤同种异体移植物的存活时间 系统性免疫抑制和 DnaK 效应的缺失取决于 SigE。因此，针对 SigE 代表 增强移植中免疫反应调节的新的潜在治疗靶点。基于 根据我们的初步数据，我们假设 SigE 是免疫反应的关键调节因子 移植。为了解决这个假设，我们提出了三个具体目标：1）定义 SigE 在 调节 DC 成熟和抗原加工； 2) 确定SigE在同种免疫和免疫中的作用 产生抗原特异性 T 细胞； 3) 研究基于以下设计的新型免疫调节分子 Siglec-9 和 DnaK 之间的相互作用。为了实现这些目标，我们将利用心脏和人性化小鼠 移植模型，一种针对 SigE 的新型合成激动剂肽，SigE 缺陷小鼠，追踪抗原特异性 T 使用过继转移细胞进行细胞染色，并使用四聚体进行内源染色。拟议的研究具有创新性 其意义重大，因为我们将探索重要的调节性先天免疫受体 SigE 的生物学 移植，我们将研究一种新的 SigE 靶向分子来抑制同种免疫，