Lymph nodes at the crossroads of allo immunity and regulation

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系统， 调变这就需要对移植同种异体免疫进行创新性的机制研究。淋巴结（LN） 同种免疫的典型器官虽然识别LN中的同种抗原是治疗的基础， 产生同种异体反应性T细胞，我们的研究小组也表明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LN的性质， 具有独特的微血管系统、基质纤维和基质细胞的极其特化的器官（称为 成纤维网状细胞[FRC]）。我们的首要假设是，操纵微环境， 淋巴结将提供一个独特的机会，指导同种免疫反应走向抗炎耐受 反应我们的主要目标是了解控制这些细胞的细胞和分子机制。 在免疫激活或耐受诱导期间LN的显微解剖适应，并高度发育 创新的治疗策略，促进调节LN微环境， 宽容该PPG为连接两个团队（Abdi博士和Bromberg博士）提供了一个平台， LN同种免疫生物学的互补技能和专业知识。项目1将检验以下假设： 同种异体免疫期间LN的FRC的持续活化将导致FRC转化为促炎性因子 肌成纤维细胞在LN内产生炎性环境，这将进一步促进同种异体免疫。我们 一个必然的假设是，恢复功能的FRC和显微解剖的LN将提高 它们的免疫调节功能和促进耐受性。目标1将研究HVEM/LIGHT的作用 在FRC分化为促炎性肌成纤维细胞的过程中， 在LN微环境内的环境和促进移植免疫。目标2将调查 纤维化FRC促进LN中促炎反应的机制。目标3将重新编程 通过FRC递送或衰老抑制剂的LN靶向递送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（LAMA 4/LAMA 5）比率的假设 并控制免疫反应的命运。目的1将明确基质细胞在控制肿瘤生长中的作用。 LAMA 4和LAMA 5的平衡。目的2明确LTβR在调节肝纤维化形成中的重要作用 LAMA 5的目的3将使用抗CD 40 L和抗LAMA 5 mAb靶向递送至LN以促进LN的免疫应答。 宽容管理核心（核心A）和纳米颗粒和FRC核心（核心B）将提供 基础设施和资源，以支持这两个项目。这些良好的整合和 高度协同的项目和核心是产生变革性的机械数据，这将奠定 为开发高度针对性和创新的移植治疗策略奠定了基础。

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.