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

靶向淋巴管中的 IKK-α 来驱动保护性三级淋巴器官的形成

• 批准号: 10667005
• 负责人: MICHAEL J MAY
• 金额: $ 23.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-24 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667005
• 关键词: Address; Adult; Animals; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Bacterial Infections; Body Weight; Body Weight decreased; Bronchus-Associated Lymphoid Tissue; CCL21 gene; Cells; Characteristics; Chemotactic Factors; Collection; Communicable Diseases; Complement; Data; Dendritic Cells; Disease; Exhibits; Gene Expression; Gene Expression Profiling; Generations; Genes; Genetic Models; Goals; Homeostasis; IKK alpha; Immune; Immune response; Immunity; Immunologics; Immunotherapy; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Knockout Mice; Lung; Lymphatic; Lymphatic Endothelial Cells; Lymphatic function; Malignant Neoplasms; Methodology; Modeling; Mus; NF-kappa B; Nature; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peripheral; Phosphotransferases; Play; Population Heterogeneity; Public Health; Pulmonary Emphysema; Research; Respiratory Tract Infections; Role; Signal Transduction; Structure; Structure of parenchyma of lung; Tamoxifen; Testing; Therapeutic; Tissues; Traction; Viral; Virus Diseases; Weight; cell assembly; cell motility; chronic inflammatory disease; cohort; design; draining lymph node; fighting; high risk; immune function; immune modulating agents; in vivo Model; influenza infection; influenzavirus; innovation; insight; lung injury; lymph nodes; lymphatic vessel; novel; novel therapeutics; prevent; prophylactic; pulmonary function; receptor; respiratory infection virus; respiratory pathogen; response; secondary lymphoid organ; single-cell RNA sequencing; tertiary lymphoid organ; therapeutic target; vaccine efficacy

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.

三级淋巴器官（TLOS）是类似于次级淋巴机构的生态结构，但 从头开始，响应感染，感染，自身免疫和癌症。 TLO功能是上下文 自身免疫性和慢性炎症性疾病的依赖，加剧的病理，同时提供免疫 细菌和病毒感染后以及各种癌症的保护。那，确定确切的信号 驱动有益TLO形成的同时避免发病机理的细胞是一个非常重要的目标，它将 定义用于开发新的免疫调节药物的新型靶标。可诱导支气管相关的淋巴样 组织（IBALT）是一种在肺部形成的TLO，以响应感染，注射和肺部形成 损坏，其功能范围从病理到保护，具体取决于 疾病。在呼吸道病毒（例如影响）感染的情况下，Ibalt提供了保护性免疫， 支持Balt形成的治疗诱导作为促进免疫力并增强疫苗的策略 肺部功效。但是，采用这种方法的主要障碍是缺乏鉴定疗法。 可以探索以促进受保护的鲍尔特形成的目标，同时避免潜在的破坏性 肺组织中的炎症反应。在我们对免疫稳态中NF-κB信号传导的持续研究中，我们 创建了在淋巴内皮细胞（LEC）中缺乏IKKA的小鼠。这些小鼠缺乏所有淋巴结，但非常明显 在没有感染，肺气肿或组织损伤的情况下形成赞助的巴尔特。感染后 流感病毒，ikka lec-ko小鼠仅瞬时减肥，所有动物都存活，而对照小鼠 体重减轻，一半以上死亡。这些发现支持了令人兴奋的新模型 在LEC中抑制IKKA会驱动非致病性巴尔特，从而通过作用提供预防性保护 作为协调快速而增强的局部抗病毒免疫响应的“指挥中心”。在此提案中 我们将利用这些新发现来解决以下假设：“针对LEC Intrinsic Ikka促进 保护性的非致病鲍尔特形成”。根据，我们将追求以下两个具体目的：（1） 确定IKKA如何调节肺淋巴血管功能； （2）建立一个新的诱导体内体内 驱动非致病巴尔特形成的模型。我们将使用此模型来确定是否限制LEC Intrinsic Ikka 删除肺部可以通过增加局部保护，同时离开淋巴结和 其他组织中的淋巴功能完整。这些研究将直接影响我们对信号的理解 调节肺淋巴机的免疫功能，并将为可行性提供至关重要的见解 治疗靶向LEC Intrinsic Ikka，以提供免疫预防性保护抗呼吸道 病原体。随着利用TLO进行免疫疗法的治疗策略正在受到关注，我们的发现将 对TLO扮演保护性免疫学作用的其他疾病具有更大的影响。