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，但排斥仍然是 长期移植损失。先天免疫激活增强了适应性免疫，并且是至关重要的参与者 沉淀急性排斥并防止移植耐受性。但是，大多数免疫抑制药物用于 诊所主要靶向T细胞，而不是先天免疫细胞。因此，有未满足的需要有效 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是一种天生的受体，可降低炎症。 SIGE用树突状细胞（DC）表达并抑制 TLRS触发的炎症反应。 SIGE的参与是促进免疫调节的有前途的策略。 但是，尚未研究SIGE在移植中的作用。我们发现缺乏sige的同种异体移植物 有加速排斥反应，肾脏移植患者的表达降低了。 （SIGLEC-9）在拒绝期间。此外，我们最近发现分枝杆菌蛋白DNAK可以与 通过下调降低DCS激活，具有强大的免疫调节作用的SIGE在同种免疫性中具有强大的免疫调节作用 MHC II和CD86。用DNAK的原位靶向供体DC能够延长皮肤同种异体移植的存活率 缺乏全身免疫抑制和DNAK效应取决于SIGE。因此，靶向sige代表 一个新型的潜在治疗靶标，可增强移植中免疫反应的调节。基于 我们的初步数据，我们假设SIGE是免疫反应的关键调节剂 移植。为了解决这一假设，我们提出了三个具体目的：1）定义SIGE在 调节直流成熟和抗原加工； 2）确定sige在同种免疫力中的作用和 产生抗原特异性T细胞； 3）研究基于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的老鼠 移植模型，一种新型的合成激动剂肽，呈sige，sige缺陷小鼠，跟踪抗原特异性T 使用收养的细胞和使用四聚体的内源性染色的细胞。拟议的研究是创新的 重要的是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，我们将研究一种新型的靶向分子以抑制同种免疫性，