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: 9238504
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238504
• 关键词: ATP Receptors; 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; Hepatic Granuloma; Human; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; KDR gene; Lesion; Lung; Lung Inflammation; Maintenance; Measures; Mediating; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Myeloid Cells; Natural Immunity; Organ; Pathogenesis; Pathology; Pathway interactions; Pharmacologic Substance; Play; Production; Proliferating; Purinoceptor; Recruitment Activity; Research; Resolution; Role; Scheme; Site; Source; Symptoms; T cell response; Technology; Testing; Tissues; Transgenes; Tuberculosis; VEGF Trap; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Virulent; angiogenesis; cancer clinical trial; cancer therapy; disease transmission; efficacy testing; experimental study; extracellular; global health; immunoreaction; improved; inhibitor/antagonist; killings; macrophage; monocyte; mycobacterial; novel; protein expression; public health relevance; pulmonary granuloma; 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 reduced the inflammatory response to infection without compromising control of bacteria. These data suggest the exciting possibility that VEGF inhibitors could lessen inflammation 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 the highly dynamic granulomas. In the second aim, we will measure the effects of VEGF inhibition on Mycobacterium tuberculosis (Mtb)-induced lung inflammation using pharmaceutical (clinically approved VEGF blockers) and genetically altered VEGF expression (LoxP-Cre mediated or transgene mediated). The effect of VEGF inhibitors will be tested on antibiotic control of the Mtb infection. We will test the hypothesis that local macrophage-induced VEGF recruits monocytes through their VEGR1 to the granulomas. 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（由适用提供）：颗粒是与结核病有关的标志性病理。这些炎症性病变含有并消除了杆菌，是生物生物损伤，分别在活性和慢性感染过程中分别增殖和持续存在。开发更好的结核病治疗的一个障碍是肉芽肿区室的生物学知识。 T细胞反应对于诱导和维持肉芽肿性免疫学很重要，但是先天免疫学的因素也调节了这些水平。我们已经观察到高水平的血管内皮生长因子（VEGF）是由分枝杆菌肉芽肿产生的，并表明VEGF抑制减少了对感染的炎症反应，而不会损害细菌的控制。这些数据表明，在结核病疾病期间，VEGF抑制剂减少炎症的可能性令人兴奋。已经通过人类临床试验对几类抑制剂进行了测试，并用于癌症疗法。调节肉芽肿性病理尤为重要，因为结核病死亡主要是侵蚀肺部和其他器官功能的压倒性病理的结果。该提案的第一个目的是检验以下假设：细胞死亡引起的ATP在肉芽肿中释放的释放驱动了产生VEGF的M2巨噬细胞的分化，这刺激了新细胞的募集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（临床认可的VEGF阻滞剂）和遗传上改变的VEGF表达（LOXP-CRE介导或转化的介导）的药物（MTB）诱导的肺部感染对VEGF抑制作用对结核分枝杆菌（MTB）诱导的肺部感染的影响。 VEGF抑制剂的作用将对MTB感染的抗生素控制进行测试。我们将检验以下假设：局部巨噬细胞诱导的VEGF通过其VEGR1募集单核细胞到颗粒瘤。在第三个目标中，我们将开发新型的巨噬细胞靶向VEGF阻滞剂。这些研究的完成将导致对肉芽肿性疾病发病机理有更好的了解，并表明对抗生素和VEGF阻滞剂的联合治疗是否可以改善结核病的治疗方法。抗VEGF疗法已经用于人类，该提案将测试是否可以扩展其使用以治疗肉芽肿性疾病。