Lymph nodes at the crossroads of allo immunity and regulation

淋巴结处于同种异体免疫和调节的十字路口

• 批准号: 10024592
• 负责人: Reza Abdi
• 金额: $ 128.93万
• 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/10024592
• 关键词: Alloantigen; Anti-Inflammatory Agents; Area; Biology; Cicatrix; Clinical; Cues; Cytoskeleton; Data; Development; Dimensions; Disease; Equilibrium; Fostering; Generations; Goals; Graft Rejection; Immune; Immune Tolerance; Immune response; Immunity; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Laminin; Mediating; Microanatomy; Modeling; Molecular; Monoclonal Antibodies; Myofibroblast; Nano delivery; Nature; Organ; Organ Transplantation; Outcome; Pathway interactions; Patients; Play; Procedures; Reaction; Regulation; Regulatory T-Lymphocyte; Research Personnel; Resources; Rest; Reticular Cell; Role; Scientist; Site; Solid; Stromal Cells; Structure; T memory cell; T-Lymphocyte; TNFSF5 gene; Technology; Testing; Therapeutic; Transplantation; Transplantation Tolerance; allograft rejection; cell transformation; combinatorial; fiber cell; high voltage electron microscopy; immune activation; immunoregulation; improved; improved outcome; inflammatory milieu; inhibitor/antagonist; innovation; isoimmunity; lymph nodes; member; nanoparticle; novel; response; restoration; senescence; skills; synergism; targeted delivery; targeted treatment

OVERALL – SUMMARY/ABSTRACT Organ transplantation remains a mainstay therapeutic strategy for patients with end organ diseases. One of the highest unmet needs to improve long-term transplant outcomes is devising more effective immune modulation. This requires innovative mechanistic studies of transplant alloimmunity. The lymph node (LN) is the quintessential organ of alloimmunity. While the recognition of alloantigens in the LN is fundamental to the generation of alloreactive T cells, our groups also have shown that the LN plays an important role in alloimmune-regulation and Treg-mediated tolerance. These multifaceted functions rest on the nature of LNs as extremely specialized organs with unique microvasculature, stromal fibers, and stromal cells (referred to as fibroblastic reticular cells [FRCs]). Our overarching hypothesis is that manipulating the microenvironment of LNs will provide a unique opportunity to direct the alloimmune reaction towards an anti-inflammatory tolerance response. Our major goals are to understand the cellular and molecular mechanisms that govern the microanatomical adaptation of the LN during immune activation or tolerance induction, and to develop highly innovative therapeutic strategies that promote a regulatory LN microenvironment and result in immune tolerance. This PPG sets forth a platform for connecting two teams (Drs. Abdi and Bromberg) with complementary skills and expertise in LN alloimmune-biology. Project 1 will test the hypothesis that sustained activation of FRCs of the LN during alloimmunity will result in FRC transformation to proinflammatory myofibroblasts creating an inflammatory milieu within the LN, which would further promote alloimmunity. Our corollary hypothesis is that restoration of the function of FRCs and microanatomy of the LNs will enhance their immunoregulatory function and promote tolerance. Aim 1 will examine the role of the HVEM/LIGHT pathway in the differentiation of FRCs into proinflammatory myofibroblasts, thereby creating an inflammatory milieu within the LN microenvironment and promoting transplant immunity. Aim 2 will investigate the mechanisms by which fibrotic FRCs promote a pro-inflammatory response in the LN. Aim 3 will reprogram the stroma of LNs via FRC delivery or LN-targeted delivery of senescence inhibitors to further promote alloimmune tolerance. Project 2 will test the hypothesis that FRCs regulate the LN laminin α4:α5 (LAMA4/LAMA5) ratio and control the fate of the immune response. Aim 1 will define the role of stromal cells in controlling the balance of LAMA4 and LAMA5. Aim 2 will define the role of LTβR as a key pathway in regulating the formation of LAMA5. Aim 3 will use targeted delivery of anti-CD40L and anti-LAMA5 mAbs to the LN to promote tolerance. An Administrative Core (Core A) and Nanoparticle and FRC Core (Core B) will provide the infrastructure and resources to support these two projects. The ultimate goal of these well-integrated and highly synergistic Projects and Cores is to generate transformative mechanistic data, which will lay the groundwork for developing highly targeted and innovative therapeutic strategies for transplantation.

总体——总结/摘要 器官移植仍然是终末器官疾病患者的主要治疗策略。之一 改善长期移植结果的最大未满足需求是设计更有效的免疫 调制。这需要对移植同种免疫进行创新的机制研究。淋巴结 (LN) 是 同种免疫的典型器官。虽然 LN 中同种异体抗原的识别对于 同种反应性 T 细胞的产生，我们的小组还表明 LN 在 同种免疫调节和 Treg 介导的耐受性。这些多方面的功能取决于逻辑网络的性质： 具有独特微血管、基质纤维和基质细胞的极其特化的器官（称为 成纤维细胞网状细胞[FRC]）。我们的首要假设是操纵微环境 LN 将提供一个独特的机会，将同种免疫反应引导至抗炎耐受性 回复。我们的主要目标是了解控制细胞和分子机制 免疫激活或耐受诱导期间 LN 的显微解剖适应，并高度发展 促进调节性淋巴结微环境并导致免疫的创新治疗策略 宽容。该 PPG 提供了一个连接两个团队（Abdi 博士和 Bromberg 博士）的平台 LN 同种免疫生物学方面的互补技能和专业知识。项目 1 将检验以下假设： 同种免疫过程中 LN 的 FRC 持续激活将导致 FRC 转化为促炎细胞 肌成纤维细胞在淋巴结内产生炎症环境，这将进一步促进同种免疫。我们的 推论假设是 FRC 功能和 LN 显微解剖结构的恢复将增强 它们的免疫调节功能并促进耐受。目标 1 将研究 HVEM/LIGHT 的作用 FRC 分化为促炎性肌成纤维细胞的途径，从而产生炎症 LN 微环境中的环境并促进移植免疫。目标 2 将调查 纤维化 FRC 促进 LN 促炎症反应的机制。目标 3 将重新编程 通过 FRC 递送或 LN 靶向递送衰老抑制剂来进一步促进同种免疫 宽容。项目 2 将检验 FRC 调节 LN 层粘连蛋白 α4:α5 (LAMA4/LAMA5) 比率的假设 并控制免疫反应的命运。目标 1 将定义基质细胞在控制 LAMA4 和 LAMA5 的平衡。目标 2 将定义 LTβR 作为调节形成的关键途径的作用 喇嘛5。目标 3 将使用抗 CD40L 和抗 LAMA5 mAb 靶向递送至 LN，以促进 宽容。管理核心（核心 A）以及纳米粒子和 FRC 核心（核心 B）将提供 支持这两个项目的基础设施和资源。这些良好集成和的最终目标 高度协同的项目和核心旨在生成变革性的机制数据，这将为 为开发高度针对性和创新的移植治疗策略奠定基础。