Innate immunity of granulomatous inflammation: the role of VEGF

 描述(申请人提供)：肉芽肿是与结核病相关的标志性病理。这些炎性病变包含和消除杆菌，是分枝杆菌在活动和慢性感染期间分别增殖和存活的生物利基。开发更好的结核病治疗方法的一个障碍是对肉芽肿间隔的生物学知之甚少。T细胞反应是诱导和维持肉芽肿性免疫的重要因素，但天然免疫因素也调节这些损害。我们观察到在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可以在不影响细菌控制的情况下减少对感染的炎症反应。这些数据表明，令人兴奋的可能性是，血管内皮生长因子抑制剂可以减轻结核病期间的炎症。几类抑制剂已经在人体临床试验中进行了测试，并被用于癌症治疗。调整肉芽肿性病理尤其重要，因为肺结核死亡主要是由侵蚀肺和其他器官功能的压倒性病理造成的。这项提议的第一个目的将检验这样一个假设，即细胞死亡诱导肉芽肿中ATP的释放驱动产生血管内皮生长因子的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(临床批准的血管内皮生长因子阻滞剂)和基因改变的血管内皮生长因子表达(loxP-Cre介导或转基因介导)来衡量血管内皮生长因子抑制对结核分枝杆菌(Mtb)诱导的肺部炎症的影响。将测试血管内皮生长因子抑制剂对结核分枝杆菌感染的抗生素控制的效果。我们将验证这样一种假设，即局部巨噬细胞诱导的血管内皮生长因子通过其VEGR1向肉芽肿招募单核细胞。在第三个目标中，我们将开发新型的巨噬细胞靶向的血管内皮生长因子阻滞剂。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，并提示抗生素和血管内皮生长因子阻滞剂的联合治疗是否可以改善结核病的治疗。抗血管内皮生长因子疗法已经在人类身上使用，该提案将测试它们的使用是否可以扩展到治疗肉芽肿疾病。

 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.