Lactoferrin Modulation of Granuloma Pathology

 描述（由申请人提供）：宿主免疫在结核病的发展中起主要作用。结核病感染者的反应是形成含有杆菌的肉芽肿。然而，肉芽肿内的生物体受到免疫介导防御的全面保护。我们假设，破坏性免疫介导的病理学的调制，同时保留必要的免疫反应，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作为免疫调节剂用于改善肉芽肿病理学的生物活性。我们的目的是确定乳铁蛋白限制破坏性病理的能力，并评估其在结核肉芽肿反应的脐带因子（糖脂海藻糖6，6 '-二霉菌酸酯; TDM）模型中的免疫调节作用。为了实现我们的目标，将用TDM静脉内激发小鼠，然后在24小时后通过口服或静脉内途径用乳铁蛋白治疗。将评价肺组织直至TDM给药后第7天的组织学和炎症介质变化。将比较给予牛乳铁蛋白或新型重组（CHO衍生）小鼠或人乳铁蛋白的小鼠之间的免疫病理学。这些研究将（1）评价口服和静脉内递送的新型重组小鼠乳铁蛋白的生物活性，以用作小鼠中的临床前研究工具，（2）验证小鼠作为物种以检查异源重组人乳铁蛋白改变结核病相关因子的病理学的活性;和（3）比较两种新的乳铁蛋白对牛乳铁蛋白（其作为可注射的人类临床治疗剂是不可接受的）的反应，以获得进行II期测试和使用毒性M.结核总的来说，这种方法代表了一种新的治疗策略，用于结核病的潜在治疗。

 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.