Innate immunity of granulomatous inflammation: the role of VEGF

肉芽肿性炎症的先天免疫：VEGF 的作用

• 批准号: 9130425
• 负责人: Matyas Sandor
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130425
• 关键词: Acute; Address; Adverse effects; Affect; Antibiotic Therapy; Antibiotics; Ants; Bacillus (bacterium); Bacteremia; Bacteria; Biological; Biology; Cell Death; Cells; Cessation of life; Chemotactic Factors; Chronic; Clinical; Clinical Trials; Data; Development; Disease; Gene Expression; Genus Mycobacterium; Granuloma; Granulomatous; Growth Factor Inhibition; Health; Hepatic Granuloma; Human; Immune; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Lead; Lesion; Life; Lung; Maintenance; Malignant Neoplasms; Measures; Mediating; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Myeloid Cells; Natural Immunity; Organ; Pathogenesis; Pathology; Pathway interactions; Pharmacologic Substance; Play; Production; Proliferating; Purinoceptor; Reaction; Recruitment Activity; Research; Resolution; Role; Scheme; Site; Source; Staging; Symptoms; T cell response; Technology; Testing; Tissues; Transgenes; Tuberculosis; VEGF Trap; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Virulent; angiogenesis; cancer therapy; disease transmission; efficacy testing; extracellular; genetic approach; global health; improved; inhibitor/antagonist; killings; macrophage; monocyte; mycobacterial; novel; protein expression; pulmonary granuloma; research study; response; tuberculosis treatment

 DESCRIPTION (provided by applicant): Granulomas are the hallmark pathology associated with tuberculosis disease. These inflammatory lesions contain and eliminate bacilli and are the biological niche where mycobacteria proliferate and persist during active and chronic infection, respectively. One roadblock to the development of better tuberculosis treatments is the poorly understood biology of the granuloma compartment. T cell response is important to induce and maintain granulomatous immunity but factors of innate immunity also regulate these lesions. We have observed high levels of Vascular Endothelial Growth Factor (VEGF) produced by macrophages in mycobacterial granulomas, and shown that VEGF inhibition reduces the inflammatory response to infection without compromising control of bacteria. These data suggest the exciting possibility that VEGF inhibitors could lessen pathology during tuberculosis disease. Several classes of inhibitors have already been tested by human clinical trials and are used in cancer therapies. Modulating granulomatous pathology is especially important since tuberculosis deaths are primarily a result of the overwhelming pathology that erodes lung and other organ function. The first aim of this proposal will test the hypothesis that cell death-induced release of ATP in the granuloma drives differentiation of VEGF-producing M2 macrophages, which stimulate the recruitment of new cells to repopulate highly dynamic granulomas. In the second aim, we will measure the effects of VEGF inhibition on Mycobacterium tuberculosis (Mtb)-induced lung pathology using pharmaceutical (clinically-used VEGF blockers) and targeted genetic approaches (LoxP-Cre mediated or transgene mediated) decreased VEGF expression. The effect of VEGF inhibitors will be tested on antibiotic control of the Mtb infection. In the third aim, we will develop novel macrophage-targeted VEGF blockers. Completion of these studies will lead to a better understanding of granulomatous disease pathogenesis and suggest whether a combined therapy of antibiotics and VEGF blockers could improve treatment of tuberculosis. Anti-VEGF therapies are already used in humans and the proposal will test whether their use may be extended to treat granulomatous diseases.

 描述（由申请人提供）：肉芽肿是与结核病相关的标志性病理学。这些炎症病变包含并消灭杆菌，并且是分枝杆菌在活动性感染和慢性感染期间分别增殖和持续存在的生物位。开发更好的结核病治疗方法的障碍之一是对肉芽肿室的生物学知之甚少。 T 细胞反应对于诱导和维持肉芽肿免疫很重要，但先天免疫因素也调节这些病变。我们观察到分枝杆菌肉芽肿中巨噬细胞产生高水平的血管内皮生长因子（VEGF），并表明抑制 VEGF 可以减少对感染的炎症反应，而不影响对细菌的控制。这些数据表明 VEGF 抑制剂可以减轻结核病期间的病理变化，这是令人兴奋的可能性。几类抑制剂已经通过人体临床试验并用于癌症治疗。调节肉芽肿病理学尤其重要，因为结核病死亡主要是侵蚀肺和其他器官功能的压倒性病理学的结果。该提案的第一个目标将检验以下假设：肉芽肿中细胞死亡诱导的 ATP 释放驱动产生 VEGF 的 M2 巨噬细胞的分化，从而刺激新细胞的招募以重新填充高度动态的肉芽肿。在第二个目标中，我们将使用药物（临床使用的 VEGF 阻滞剂）和靶向遗传方法（LoxP-Cre 介导或转基因介导）降低 VEGF 表达，测量 VEGF 抑制对结核分枝杆菌 (Mtb) 诱导的肺部病理学的影响。将测试 VEGF 抑制剂对抗生素控制 Mtb 感染的效果。第三个目标是开发新型巨噬细胞靶向 VEGF 阻断剂。这些研究的完成将有助于更好地了解肉芽肿性疾病的发病机制，并表明抗生素和 VEGF 阻滞剂的联合治疗是否可以改善结核病的治疗。抗 VEGF 疗法已用于人类，该提案将测试其用途是否可以扩展到治疗肉芽肿性疾病。