Targeting IKK-alpha in lymphatics to drive protective tertiary lymphoid organ formation

三级淋巴器官(TLO)是一种异位结构，类似于二级淋巴器官，但 对感染、炎症、自身免疫和癌症的反应从头开始。TLO函数是上下文 依赖、加剧自身免疫和慢性炎症性疾病的病理，同时提供免疫 在细菌和病毒感染后，以及在各种癌症中的保护。因此，识别准确的信号 在避免发病的同时推动有益的TLO形成的细胞是一个非常重要的目标，它将 为开发新的免疫调节药物确定新的目标。可诱导的支气管相关淋巴组织 组织(IBALT)是一种在肺部对感染、炎症和肺部反应形成的TLO 损害，其功能范围从病理性到保护性，取决于 疾病。在感染流感等呼吸道病毒的情况下，iBALT提供保护性免疫， 支持治疗性诱导BALT形成作为促进免疫和增强疫苗的策略 对肺的功效。然而，推行这一方法的一个主要障碍是缺乏已确定的治疗方法。 可以利用的目标，以促进保护性弹道的形成，同时避免潜在的破坏性 肺组织的炎症反应。在我们正在进行的NF-κB信号在免疫动态平衡中的研究中，我们 建立了淋巴管内皮细胞(LECs)中缺乏Ikka的小鼠。这些小鼠没有所有的淋巴结，但值得注意的是 在没有炎症、肺气肿或组织损伤的情况下形成自发性BALT。在感染了 流感病毒，Ikka LEC-KO小鼠只是暂时体重下降，所有动物都存活了下来，而对照组小鼠 体重大幅下降，超过一半的人死亡。这些发现支持了一个令人兴奋的新模型，在这个模型中 抑制晶状体上皮细胞中的Ikka将驱动非致病性的BALT，从而通过作用提供预防性保护 作为“指挥中心”，协调快速和增强的局部抗病毒免疫反应。在本建议书中 我们将利用这些新的发现来解决这样的假设，即针对LEC固有的Ikka促进 保护性的非致病性Balt形成“。因此，我们会追求以下两个具体目标：(1) 确定Ikka如何调节肺淋巴管功能；(2)在体内建立新的诱导剂 驱动非致病性BALT形成的模型。我们将使用此模型来确定是否限制LEC固有的Ikka 删除肺部可以通过增加局部保护来增强保护，同时离开淋巴和 其他组织的淋巴功能完好无损。这些研究将直接影响我们对以下信号的理解 调节肺淋巴管的免疫功能，并将为研究 以LEC固有的Ikka为靶点提供呼吸道免疫预防保护 病原体。随着利用TLO进行免疫治疗的治疗策略正在获得支持，我们的发现将 对TLO发挥保护性免疫作用的其他疾病有更广泛的影响。

Tertiary lymphoid organs (TLOs) are ectopic structures that resemble secondary lymphoid organs, but arise de novo in response to infection, inflammation, autoimmunity and cancer. TLO function is context dependent, exacerbating pathology of autoimmune and chronic inflammatory diseases, while providing immune protection following bacterial and viral infections, and in various cancers. Thus, identifying the precise signals and cells that drive beneficial TLO formation while avoiding pathogenesis is a highly significant objective that will define novel targets for developing new immune-modulating drugs. Inducible bronchus-associated lymphoid tissue (iBALT) is a type of TLO that forms in the lungs in response to infection, inflammation and pulmonary damage, where its function ranges from pathologic to protective depending on the nature and context of the disease. In the case of infection by respiratory viruses such as influenza, iBALT provides protective immunity, supporting therapeutic induction of BALT formation as a strategy to promote immunity and enhance vaccine efficacy in the lung. However, a major roadblock to pursuing this approach is the lack of identified therapeutic targets that can be exploited to promote protective BALT formation while avoiding potentially destructive inflammatory responses in lung tissue. In our ongoing studies of NF-κB signaling in immune homeostasis, we created mice lacking IKKa in lymphatic endothelial cells (LECs). These mice lack all lymph nodes, but remarkably form spontaneous BALT in the absence of inflammation, emphysema or tissue damage. Following infection with influenza virus, IKKa LEC-KO mice only transiently lost weight and all animals survived, whereas control mice lost extensive body weight and more than half died. These findings support an exciting new model in which inhibition of IKKa in LECs would drive non-pathogenic BALT, thereby providing prophylactic protection by acting as a “command center” to coordinate a rapid and enhanced local anti-viral immune response. In this proposal we will leverage these new findings to address the hypothesis that “targeting LEC-intrinsic IKKa promotes protective non-pathogenic BALT formation”. Accordingly, we will pursue the following two specific aims: (1) To determine how IKKa regulates pulmonary lymphatic vessel function; (2) To establish a new inducible in vivo model to drive non-pathogenic BALT formation. We will use this model to determine if limiting LEC-intrinsic IKKa deletion to the lungs can augment protection by increasing local protection, while leaving lymph node and lymphatic function in other tissues intact. These studies will directly impact our understanding of the signals that regulate the immune function of pulmonary lymphatics and will provide crucial insight into the feasibility of therapeutically targeting LEC-intrinsic IKKa to provide immunoprophylactic protection against respiratory pathogens. As therapeutic strategies to exploit TLOs for immunotherapy are gaining traction, our findings will have a wider impact for other diseases in which TLOs play a protective immunological role.