HVEM pathway regulating FRC function and transplant tolerance

摘要 淋巴结节(LNS)是免疫的典型器官。我们对LNS控制方式的理解 同种异体免疫反应随着最近的进展而显著进化，这些进展突显了特异性免疫反应的功能 LN的细胞和间质成分。LN中供体同种异体抗原对受体T细胞的呈递 是启动同种异体反应性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， 这一普遍概念的新维度是，LN对于移植耐受也是至关重要的。 这些多方面的职能反映了国土安全部作为极其专门的机构的地位，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间质隔室 称为成纤维细胞网状细胞(FRC)。这个项目的总体假设是持续的激活 移植后引流层(DLN)中FRCs的变化导致其转化为促进瘢痕形成的过程。 炎性肌成纤维细胞，进一步促进同种异体免疫。我们的研究将机械地集中在 LIGH/HVEM信号通路在FRC分化为促炎细胞中的重要作用 移植后LN中的肌成纤维细胞。我们的推论是恢复原生生物 FRCs通过靶向递送药物至LNS的功能将增强其免疫调节功能 提倡宽容。我们提出的三个目标如下：在目标1中，我们将研究 LIGH/HVEM途径在调节FRC功能、控制细胞外基质(ECM)积聚中的作用 以及调解移植免疫力。使用全局光和HVEM基因敲除小鼠，以及具有条件性 HVEM在FRC上的敲除，我们将获得关于光/HVEM通路如何控制FRC的机械性见解 FRCs的分化和移植结果。在目标2中，我们将研究衰老的重要性 测定FRCs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 促进移植后的同种异体免疫。在目标3中，我们将确定是否提供健康的FRC DLN的感觉剂将恢复其微结构，并调节同种异体免疫 移植。这些研究的数据将首次为开发创新产品奠定基础 旨在操纵LNS内微环境的治疗策略。这提供了一种独特的 有机会引导移植后的同种免疫反应向耐受方向发展。这项建议 建立一个多学科协作团队，以产生新的机械数据，这将提供 为高度创新和选择性的移植治疗策略奠定了基础。因此，这项建议可以 在器官移植领域取得革命性进展。

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.