HVEM pathway regulating FRC function and transplant tolerance

HVEM 通路调节 FRC 功能和移植耐受

• 批准号: 10662313
• 负责人: Reza Abdi
• 金额: $ 52.05万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-27 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662313
• 关键词: Adopted; Alloantigen; Anti-Inflammatory Agents; Cell Aging; Cell Transplantation; Cell physiology; Cells; Characteristics; Cicatrix; Clinical; Collagen; Cues; Data; Dendritic Cells; Deposition; Dimensions; Drug Delivery Systems; Drug Targeting; Equilibrium; Extracellular Matrix; Fibronectins; Fibrosis; Future; Generations; Goals; Graft Rejection; Heart Transplantation; Homing; Immune Targeting; Immunity; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knock-out; Knockout Mice; Light; Mediating; Mesenchymal; Molds; Mus; Myofibroblast; Organ; Organ Transplantation; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Play; Positioning Attribute; Process; Production; Property; Reaction; Regulation; Regulatory T-Lymphocyte; Reticular Cell; Role; Signal Pathway; Signal Transduction; Stromal Cells; Structure; Supporting Cell; Surface; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Transplantation; Transplantation Tolerance; allograft rejection; chemokine; conditional knockout; cytokine; draining lymph node; high voltage electron microscopy; immunoregulation; in vivo; infancy; innovation; insight; isoimmunity; lymph node microenvironment; lymph nodes; multidisciplinary; novel; prevent; programs; public health relevance; response; restoration; senescence; standard care; transplant model; transplantation therapy

Abstract Lymph nodes (LNs) are the quintessential organs of immunity. Our understanding of how LNs control alloimmune responses has evolved significantly with recent advances which highlight the function of specific cellular and stromal components of the LN. Presentation of donor alloantigen to recipient T cells in the LN is fundamental to the priming of allo-reactive T cells and subsequent allograft rejection. A recently recognized, new dimension to this pervasive concept is that the LN is also critically important for transplant tolerance. These multifaceted functions reflect the status of LNs as extremely specialized organs with unique microvasculature, and a stromal compartment that is molded and regulated by resident mesenchymal cells known as fibroblastic reticular cells (FRCs). The overall hypothesis of this project is that sustained activation of FRCs in the draining LN (DLN) following transplantation results in their transformation to scar-forming pro- inflammatory myofibroblasts, which further promote alloimmunity. Our studies will focus mechanistically on the importance of the LIGHT/HVEM signaling pathway to the differentiation of FRCs into proinflammatory myofibroblasts in the LN following transplantation. Our corollary hypothesis is that restoration of the native function of FRCs through targeted drug delivery to LNs will enhance their immunoregulatory function and promote tolerance. We are proposing three AIMS as follows: In AIM 1, we will examine the role of the LIGHT/HVEM pathway in regulating the function of FRCs, controlling extracellular matrix (ECM) accumulation, and mediating transplant immunity. Using global LIGHT and HVEM knockout mice, and mice with conditional knockout of HVEM on FRCs, we will gain mechanistic insights into how the LIGHT/HVEM pathway controls the differentiation of FRCs and transplantation outcomes. In AIM 2, we will study the importance of senescence in determining the balance between the pro-inflammatory and anti-inflammatory properties of FRCs. We will use a number of innovative conditional knockout mice to decipher the mechanisms by which senescent FRCs promote alloimmunity following transplantation. In AIM 3, we will determine whether delivering healthy FRCs and senolytic agents to the DLN will restore its microarchitecture and regulate alloimmunity following transplantation. The data from these studies will lay the groundwork for the first time to develop innovative therapeutic strategies aimed at manipulating the microenvironment within LNs. This provides a unique opportunity to direct the alloimmune response following transplantation towards tolerance. This proposal establishes a multidisciplinary collaborative team to produce novel mechanistic data, which will provide the basis for highly innovative and selective therapeutic strategies for transplantation. Therefore, this proposal can make transformative advances in the field of organ transplantation.

抽象的 淋巴结（LN）是典型的免疫器官。我们对 LN 如何控制的理解 同种免疫反应随着最近的进展而发生了显着的变化，这些进展突出了特定免疫反应的功能。 LN 的细胞和基质成分。供体同种抗原在 LN 中呈递给受体 T 细胞的过程是 对于同种异体反应性 T 细胞的启动和随后的同种异体移植排斥至关重要。最近认识到， 这一普遍概念的新维度是，淋巴结对于移植耐受性也至关重要。 这些多方面的功能反映了 LN 作为极其专业的器官的地位，具有独特的 微血管系统，以及由常驻间充质细胞塑造和调节的基质室 称为成纤维网状细胞（FRC）。该项目的总体假设是持续激活 移植后引流淋巴结（DLN）中的 FRC 会转化为疤痕形成前体。 炎症肌成纤维细胞，进一步促进同种免疫。我们的研究将机械地集中于 LIGHT/HVEM 信号通路对 FRC 分化为促炎细胞的重要性 移植后 LN 中的肌成纤维细胞。我们的推论假设是，原生环境的恢复 通过向 LN 靶向给药，FRC 的功能将增强其免疫调节功能， 促进宽容。我们提出以下三个目标： 在目标 1 中，我们将研究 LIGHT/HVEM 通路调节 FRC 功能，控制细胞外基质 (ECM) 积累， 和介导移植免疫。使用全局 LIGHT 和 HVEM 基因敲除小鼠以及条件小鼠 敲除 FRC 上的 HVEM，我们将获得有关 LIGHT/HVEM 通路如何控制 FRC 的分化和移植结果。在 AIM 2 中，我们将研究衰老的重要性 确定 FRC 的促炎和抗炎特性之间的平衡。我们将使用 一些创新的条件敲除小鼠来破译衰老 FRC 的机制 促进移植后的同种免疫。在 AIM 3 中，我们将确定是否提供健康的 FRC DLN 的抗衰老剂将恢复其微结构并调节同种免疫 移植。这些研究的数据将为首次开发创新奠定基础 旨在操纵 LN 内微环境的治疗策略。这提供了一个独特的 有机会引导移植后的同种免疫反应走向耐受。这个提议 建立一个多学科协作团队来产生新颖的机械数据，这将提供 高度创新和选择性移植治疗策略的基础。因此，本提案可以 在器官移植领域取得革命性进展。