Innate immunity of granulomatous inflammation: the role of VEGF

 描述（由申请人提供）：肉芽肿是与结核病相关的标志性病理。这些炎性病变包含并消除杆菌，并且分别是活动性和慢性感染期间分枝杆菌增殖和持续存在的生物生态位。发展更好的结核病治疗的一个障碍是对肉芽肿室的生物学知之甚少。T细胞应答对于诱导和维持肉芽肿免疫是重要的，但先天免疫因子也调节这些病变。我们已经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），并且表明VEGF抑制减少了对感染的炎症反应而不损害对细菌的控制。这些数据表明，VEGF抑制剂可能会减轻结核病的病理过程中令人兴奋的可能性。几类抑制剂已经通过人体临床试验进行了测试，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。本提案的第一个目的是检验肉芽肿中细胞死亡诱导的ATP释放驱动产生VEGF的M2巨噬细胞分化的假设，M2巨噬细胞刺激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（临床使用的VEGF阻断剂）和靶向遗传方法（LoxP-Cre介导或转基因介导）降低VEGF表达来测量VEGF抑制对结核分枝杆菌（Mtb）诱导的肺病理学的影响。将测试VEGF抑制剂对Mtb感染的抗生素控制的作用。在第三个目标中，我们将开发新的巨噬细胞靶向VEGF阻断剂。这些研究的完成将导致更好地了解肉芽肿性疾病的发病机制，并建议抗生素和VEGF阻滞剂的联合治疗是否可以改善结核病的治疗。抗VEGF疗法已经用于人类，该提案将测试其用途是否可以扩展到治疗肉芽肿性疾病。

 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.