Lactoferrin Modulation of Granuloma Pathology

 描述(申请人提供)：宿主免疫在结核病的发生发展中起主要作用。结核病感染者的反应是形成肉芽肿，肉芽肿中含有杆菌。然而，肉芽肿内的生物体受到保护，不受免疫调节防御的全面影响。我们假设，破坏性免疫介导的病理的调节，在保留基本免疫反应的同时，将允许更有效的免疫控制。因此，这些研究的目的是评估新型重组小鼠和人乳铁蛋白的生物活性，以用作免疫调节剂来改善肉芽肿病理。我们的目的是确定乳铁蛋白限制破坏性病理的能力，并评估其在脐带因子(糖脂海藻糖，6，6‘-二聚乙醇酸；TDM)结核病肉芽肿反应模型中的免疫调节作用。为了实现我们的目标，小鼠将被静脉注射TDM，然后在24小时后通过口服或静脉注射乳铁蛋白进行治疗。肺组织将通过TDM给药后第7天的组织学和炎症介质的变化进行评估。免疫病理学将在给予牛乳铁蛋白的小鼠和新型重组(CHO衍生)小鼠或人乳铁蛋白之间进行比较。这些研究将(1)评估口服和静脉注射新型重组小鼠乳铁蛋白的生物活性，以用作小鼠(同源)系统改变肉芽肿反应的临床前研究工具；(2)验证小鼠作为检测异源重组人乳铁蛋白改变结核病相关因素的病理活性的物种的有效性；以及(3)比较两种新型乳铁蛋白对牛乳铁蛋白的响应(这两种乳铁蛋白不能被接受作为可注射的人类临床治疗手段)，以获得推进第二阶段测试和利用强毒结核分枝杆菌挑战的信心。总体而言，这种方法代表了潜在治疗结核病的一种新的治疗策略。

 DESCRIPTION (provided by applicant): Host immunity plays a major role in development of Tuberculosis disease. Tuberculosis infected individuals respond by formation of granulomas, which contain bacilli. However, organisms within granulomas are protected from the full scope of immune-mediated defenses. We hypothesize that modulation of destructive immune-mediated pathology, while preserving essential immune responses, will allow more effective immune control. The goal of these studies is therefore to assess bioactivity of novel recombinant mouse and human lactoferrins for use as immune modulators to ameliorate granuloma pathology. Our aims are to determine lactoferrin's ability to limit destructive pathology, and to evaluate its immune modulatory effects in the cord factor (glycolipid trehalose 6,6'-dimycolate; TDM) model of tuberculosis granulomatous response. To accomplish our goal, mice will be challenged iv with TDM, and then treated with lactoferrin via oral or iv route 24 hours later. Lung tissue will be evaluated through day 7 post TDM administration for changes in histology and inflammatory mediators. Immunopathology will be compared between mice given bovine lactoferrin, or novel recombinant (CHO-derived) mouse or human lactoferrins. These studies will (1) evaluate bioactivity of oral and intravenous delivered novel recombinant mouse lactoferrin for use as a preclinical research tool in a mouse (homologous) system to alter granuloma responses; (2) validate the mouse as a species to examine activity of heterologous recombinant human lactoferrin to alter pathology to tuberculosis-related factors; and (3) compare responses of both novel lactoferrins to bovine lactoferrin (which is not acceptable as an injectable human clinical therapeutic), to achieve confidence to move forward with Phase II testing and challenge using virulent M. tuberculosis. Overall, this approach represents a novel therapeutic strategy for potential treatment of tuberculosis disease.