HVEM pathway regulating FRC function and transplant tolerance

摘要 淋巴结（LN）是免疫的典型器官。我们对LN如何控制 同种免疫应答随着最近的进展而显著发展，这些进展突出了特异性免疫应答的功能。 LN的细胞和基质成分。LN中供者同种异体抗原向受者T细胞的提呈 这是引发同种异体反应性T细胞和随后的同种异体移植排斥反应的基础。一个最近被认可的， 这个普遍概念的新维度是LN对于移植耐受性也是至关重要的。 这些多方面的职能反映了法律网络作为极其专门化的机构的地位， 微血管系统，以及由常驻间充质细胞塑造和调节的基质隔室 称为成纤维细胞网状细胞（FRC）。这个项目的总体假设是， 移植后引流LN（DLN）中的FRC导致其转化为瘢痕形成前体， 炎性肌成纤维细胞，其进一步促进同种异体免疫。我们的研究将机械地集中在 LIGHT/HVEM信号通路对FRCs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， 通过靶向药物递送至LN的FRC功能将增强其免疫调节功能， 促进宽容。我们提出了三个目标，具体如下：在目标1中，我们将研究 LIGHT/HVEM通路在调节FRC的功能，控制细胞外基质（ECM）的积累， 和介导移植免疫。使用整体LIGHT和HVEM敲除小鼠，以及具有条件刺激的小鼠， 通过敲除FRCs上的HVEM，我们将获得关于LIGHT/HVEM通路如何控制FRCs的机制的见解。 FRC的分化和移植结果。在AIM 2中，我们将研究衰老在 确定FRC的促炎和抗炎性质之间的平衡。我们将使用 一些创新的条件性基因敲除小鼠来破译衰老的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 和衰老清除剂的DLN将恢复其微结构和调节同种异体免疫， 移植这些研究的数据将首次为开发创新的 治疗策略旨在操纵LN内的微环境。这提供了一个独特的 有机会将移植后的同种免疫反应导向耐受。这项建议 建立了一个多学科的合作团队，以产生新的机械数据，这将提供 高度创新和选择性移植治疗策略的基础。因此，这项建议可以 在器官移植领域取得革命性的进展。

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.