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

三级淋巴器官（TLO）是类似于二级淋巴器官的异位结构，但 由于感染、炎症、自身免疫和癌症而重新出现。TLO功能是上下文 依赖性，加重自身免疫性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各种癌症中的保护作用。因此，识别精确的信号 和驱动有益的TLO形成同时避免发病机制的细胞是一个非常重要的目标， 为开发新的免疫调节药物定义新的靶点。诱导型支气管相关淋巴样 组织（iBALT）是一种TLO类型，其响应于感染、炎症和肺部炎症而在肺中形成。 损害，其功能范围从病理性到保护性，取决于损害的性质和背景。 疾病在流感等呼吸道病毒感染的情况下，iBALT提供保护性免疫， 支持BALT形成的治疗性诱导，作为促进免疫和增强疫苗的策略 在肺部的功效。然而，追求这种方法的一个主要障碍是缺乏确定的治疗方法。 可用于促进保护性BALT形成的靶，同时避免潜在的破坏性 肺组织的炎症反应。在我们正在进行的免疫稳态中NF-κB信号转导的研究中，我们 在淋巴管内皮细胞（LEC）中产生缺乏IKKa的小鼠。这些老鼠没有淋巴结，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。感染后 流感病毒感染后，IKKa LEC-KO小鼠仅短暂减轻体重，所有动物均存活，而对照小鼠 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， 抑制LEC中的IKKa将驱动非致病性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。本提案中 我们将利用这些新的发现来解决“靶向LEC-内在IKKa促进 保护性非致病性BALT形成”。因此，我们将追求以下两个具体目标：（1） 研究IKKa对肺淋巴管功能的调节作用;（2）建立一种新的可诱导的 驱动非致病性BALT形成的模型。我们将使用这个模型来确定是否限制LEC-内在IKKa 肺的缺失可以通过增加局部保护来增强保护，同时留下淋巴结， 其他组织的淋巴功能完好。这些研究将直接影响我们对信号的理解， 调节肺动脉粥样硬化的免疫功能，并将为肺动脉粥样硬化的可行性提供重要的见解。 治疗性靶向LEC-内源性IKKa以提供针对呼吸道感染的免疫预防性保护 病原体随着利用TLO进行免疫治疗的治疗策略越来越受到关注，我们的研究结果将 对其他疾病具有更广泛的影响，其中TLO发挥保护性免疫作用。

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.