Lactoferrin Modulation of Granuloma Pathology

乳铁蛋白对肉芽肿病理学的调节

基本信息

批准号：
8901558
负责人：
JEFFREY K ACTOR
金额：
$ 22.47万
依托单位：
PHARMAREVIEW CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901558
关键词：
Affect Animal Model Antitubercular Agents Bacillus (bacterium)Bacteria Biological Assay Biological Models Cattle Clinical Cord Factors Development Disease Effector Cell Environment Future Genetic Transcription Glycolipids Goals Granuloma Granulomatous Histology Hour Human Immune Immune response Immunity Individual Infection Inflammation Mediators Inflammatory Injectable Intravenous Laboratories Lactoferrin Lead Mediating Modality Modeling Mus Mycobacterium tuberculosis Oral Organism Outcome Pathology Penetration Phase Play Population Pre-Clinical Model Production Proteins Recombinants Regimen Research Role Route Structure of parenchyma of lung Surface System Testing Therapeutic Trehalose Tuberculosis Virulent chemokine cytokine experience immunopathology immunoregulation in vivo innovation killings macrophage mouse model mycobacterial novel novel therapeutics phase 1 study pre-clinical research prevent public health relevance research study response tool treatment strategy tuberculosis granuloma tuberculosis treatment

项目摘要

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.

描述（由适用提供）：宿主免疫在结核病发育中起重要作用。结核病感染的个体通过形成含有杆菌的肉芽肿而反应。但是，颗粒内的生物受到免疫介导的防御范围的全部范围。我们假设对破坏性免疫介导的病理的调节，同时保留必要的免疫复杂，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，以改善肉芽肿病理学。我们的目的是确定乳铁蛋白限制破坏性病理学的能力，并评估其在脐带因子（糖脂三甲糖6,6'-二氨基酸糖）模型中的免疫调节作用。为了实现我们的目标，将用TDM挑战小鼠IV，然后在24小时后通过口服或IV路线用乳铁蛋白治疗。肺组织将在TDM后第7天对组织学和炎症介质的变化进行评估。将牛乳铁蛋白或新型重组（CHO衍生的）小鼠或人乳铁蛋白的小鼠之间的免疫病理学比较。这些研究将（1）评估口服和静脉注射的新型重组小鼠乳铁罗林的生物活性，以用作小鼠（同源）系统中的临床前研究工具，以改变肉芽肿反应；（2）将小鼠作为一种物种验证，以检查异源重组人乳铁蛋白的活性，以改变与结核病相关的因素的病理；（3）比较两种新型乳铁蛋白与牛乳铁蛋白的反应（这是不可接受的可注射人类临床疗法），以实现信心，使用毒性结核分枝杆菌进行II期测试和挑战。总体而言，这种方法代表了一种用于结核病潜在治疗的新型治疗策略。