Mechanisms that alter lymphatic transport in inflammatory bowel disease

改变炎症性肠病淋巴运输的机制

• 批准号: 10565928
• 负责人: Gwendalyn J Randolph
• 金额: $ 56.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565928
• 关键词: Address; Affect; Anti-Tumor Necrosis Factor Therapy; B-Lymphocytes; Biogenesis; Cells; Complex; Crohn' s disease; Data; Disease; Disease Progression; Encapsulated; Endothelium; Environment; Functional disorder; Gene Expression; Genes; Histologic; Ileitis; Image; Immune; Immunize; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Laboratory Study; Left; Ligands; Localized Disease; Lymph; Lymphangiogenesis; Lymphangitis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphoid; Maintenance; Mediator; Mesentery; Messenger RNA; Mus; Muscle; Muscular Atrophy; Mutation; Nature; Obstruction; Pathology; Pathway interactions; Patients; Phenotype; Receptors, Tumor Necrosis Factor, Type II; Research; Resected; Role; Running; Signal Transduction; Site; Skeletal Muscle; Source; Systemic disease; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Testing; Thinness; Tissues; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Tumor Necrosis Factors; bone; bone loss; cytokine; draining lymph node; human tissue; ileum; in vivo; lymph flow; lymph nodes; lymphatic circulation; lymphatic drainage; lymphatic dysfunction; lymphatic valve; lymphatic vasculature; lymphatic vessel; mesenteric lymphatics; mouse model; neutralizing monoclonal antibodies; predictive modeling; pressure; prevent; programs; single cell sequencing; tertiary lymphoid organ; trafficking

ABSTRACT Reactive lymphangiogenesis requires B cell-expressed lymphotoxin (LT)α. LTα signals through TNFR1 or TNFR2 when it is presented to cells as a LTα3 homotrimer, or it signals through LTβR when it is part of the LTa1b2 heterotrimeric complex. Lymphangitis has been described as a feature of Crohn's disease, but the nature and role of lymphangitis in the disease has not been elucidated. In resected tissue from Crohn's disease patients, outflow lymphatic trunks (called collecting lymphatic vessels) running from the ileum through the mesentery and on to draining lymph nodes appeared obstructed by tertiary lymphoid organs (TLOs) that formed around them. The TLOs were rich in B cells. In a mouse model of ileitis driven by a mutation in the mRNA locus for the cytokine TNF (TNF∆ARE mice) that increases TNF abundance when the gene is environmentally triggered, TLOs developed along mesenteric collecting lymphatics draining the ileum, like patients. The mice display marked blockade of lymph flow due to obstruction by the TLOs, which raised lymph pressure so that flow did not move forward but pushed backwards through lymphatic collaterals toward the gut. Backflow characterizes compromised valves. Indeed, TLOs mainly formed where lymphatic valves lost their identity and quiescence. Instead, these valve sites supported lymphangiogenesis that partially encapsulated expanding TLOs. Before lymphangiogenesis got underway, B cells accumulated around lymphatic valves. These B cells may be the source of cytokines that act on the lymphatic vessels. Indeed, data so far suggest that the action of TNF on lymphatic endothelium may be sufficient in vitro and in vivo to reprogram valve- associated genes critical to the maintenance of normal lymph flow. That is, early blockade with anti-TNF neutralizing mAb restores lymph flow and prevents progression of TLOs. At late stages in disease, anti-TNF therapy becomes less effective as the TLOs have greatly expanded and enlarged, but nonetheless anti-TNF still partially restores mesenteric lymph flow, suggesting that TNF remains a key, and possibly required, signal in disease progression. However, it remains unclear if the TLOs per se drive worsened ileitis. What would happen if the TLOs did not form but other inflammatory pathways were left intact? In preliminary data for this application, we have identified a means to prevent TLO formation: TLOs do not form in the absence of B cells. Furthermore, TNF and/or LTα expressed by B cells is required for the formation of TLOs in the ileitis-affected mesentery of TNFARE mice. These data cause us to hypothesize that TNF receptor ligands TNF and/or LTα derived from B cells act through TNF receptors on lymphatic endothelium to drive tertiary lymphoid organ (TLO) formation by skewing signals that normally maintain lymphatic valve integrity. We predict, in turn, that TLOs govern the pathophysiology of the disease itself by trapping inflammatory cells and mediators rather than allowing such mediators to disseminate and enhance systemic pathology. This model predicts a Catch-22 feature of TLOs: they protect against some forms of pathology but drive others.

摘要 反应性淋巴管生成需要B细胞表达的光敏素（LT）α。LTα信号通过TNFR 1或 当TNFR 2作为LTα3同源三聚体呈递给细胞时，或者当它是TNF α 3同源三聚体的一部分时，它通过LTβR发出信号。 LTa 1b 2异源三聚体复合物。淋巴管炎被描述为克罗恩病的一个特征，但 淋巴管炎在疾病中的性质和作用尚未阐明。从克罗恩病切除的组织中 疾病患者，流出淋巴干（称为收集淋巴管）从回肠通过 肠系膜和引流淋巴结似乎被三级淋巴器官（TLO）阻塞， 在他们周围形成。TLO富含B细胞。在小鼠回肠炎模型中， 细胞因子TNF（TNF α ARE小鼠）的mRNA基因座，当基因表达时，该基因座增加TNF丰度。 环境触发的，TLO沿着肠系膜收集血管发展，引流回肠，如 患者由于TLO的阻塞，小鼠显示出明显的淋巴流阻塞， 压力，使流动不向前移动，而是向后推动通过淋巴侧枝向肠道。 回流是受损瓣膜的特征。事实上，TLO主要形成于淋巴阀失去其功能的地方。 同一性和静止。相反，这些瓣膜部位支持部分包裹的淋巴管生成， 扩大TLO。在淋巴管形成之前，B细胞聚集在淋巴管周围。 这些B细胞可能是作用于淋巴管的细胞因子的来源。事实上，迄今为止的数据表明， TNF对淋巴管内皮的作用可能足以在体外和体内重新编程瓣膜- 相关基因对维持正常淋巴液流动至关重要。即早期用抗TNF阻断 中和mAb恢复淋巴流动并防止TLO进展。在疾病的晚期，抗TNF 治疗变得不那么有效，因为TLO已经大大扩展和扩大，但是抗TNF 仍然部分恢复肠系膜淋巴液流动，表明TNF仍然是一个关键的，可能是必需的信号 在疾病进展中。然而，目前尚不清楚TLO本身是否会导致回肠炎恶化。会怎么 如果TLO没有形成，但其他炎症通路完好无损，会发生什么？初步数据显示， 在本申请中，我们已经确定了一种防止TLO形成的方法：在没有B细胞的情况下不形成TLO。 此外，由B细胞表达的TNF和/或LTα是受回肠炎影响的患者中形成TLO所必需的。 TNF α ARE小鼠的肠系膜。这些数据使我们推测TNF受体配体TNF和/或LTα 来源于B细胞，通过淋巴管内皮上的TNF受体驱动三级淋巴器官 (TLO)通过扭曲通常维持淋巴瓣完整性的信号形成。我们预测，反过来， TLO通过捕获炎性细胞和介质而不是通过抑制炎症细胞和介质来控制疾病本身的病理生理学。 使这些介质扩散并增强系统病理学。这个模型预测了一个第二十二条军规 TLO的一个特点是：它们保护免受某些形式的病理，但驱动其他形式的病理。