DETERMINANTS OF PROTECTIVE IMMUNITY TO TUBERCULOSIS

结核病保护性免疫力的决定因素

• 批准号: 7716306
• 负责人: Deepak Kaushal
• 金额: $ 1.39万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-21 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716306
• 关键词: Animals; Calmette-Guerin Bacillus; Chronic; Computer Retrieval of Information on Scientific Projects Database; Control Animal; Control Groups; Disease; Evaluation; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Grant; Human; Human Characteristics; IL8 gene; Immune system; Immunity; Infection; Institution; Interferon Type II; Interleukin-17; Interleukin-6; Lesion; Localized; Lung; Macaca; Macrophage Inflammatory Proteins; Modeling; Molecular; Outcome; Physiological; Pilot Projects; Play; Range; Research; Research Personnel; Resources; Role; Saline; Site; Source; Statistically Significant; Structure of parenchyma of lung; System; Tissue Sample; Tissues; Tuberculosis; Tuberculosis Vaccines; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; immune function; nonhuman primate; response; transcriptomics

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A new, more effective vaccine is clearly essential for the long-term control of TB. We contend that it is crucial to identify the correlates of protection for TB, in the context of BCG vaccination, and to utilize this information during the search for future anti-TB vaccines. Nonhuman Primates (NHPs) are excellent models of TB due to their genetic, genomic and physiological similarity with humans. NHPs develop human-like disease with various outcomes, ranging from active to chronic to latent disease and display an entire spectrum of pathological features characteristic of human TB. Six macaques, intradermally vaccinated with BCG (Danish; 50 x 10E6), and a control group (saline) were challenged with 1000 CFU of Mtb Erdman, via bronchoscopic instillation, eight months after vaccination. As part of this pilot project, we obtained lung tissue from all the above animals, and used these tissue samples to perform system-wide transcriptomic studies. We compared: i) Gene-expression in lung lesion(s) of control animals to non-lesion tissues from the same animal (transcriptome comparison of NHP lung response to Mtb infection); ii) Gene-expression in lung lesion(s) of BCG-vaccinated animals to non-lesion tissues from the same animal (transcriptome comparison of modulation in NHP lung response to Mtb infection); and iii) Gene-expression in lung lesion(s) of BCG-vaccinated animals to lung lesions from control animals (transcriptomic evaluation of the effect of BCG vaccination on the NHP lung response to Mtb infection). We identified a small, discrete group of genes whose expression was perturbed in a statistically significant manner, as a result of BCG vaccination. Immune function genes such as FoxP3, MIP, IL-6 and IL-24, which were expressed in both vaccinated and control groups, as well as IFN-gamma, IL-8, IL-21beta, IL-17, IL-27 and RANTES, which were specifically expressed, only in BCG vaccinated animal lungs. Our results clearly indicate that vaccination with BCG clearly and effectively modulates the immune system at the site of Mtb infection. Some of these changes may play a role in inducing localized protection from Mtb infection. It is important to characterize the changes observed following BCG vaccination, in our preliminary studies, in order to identify key molecular correlates of protection from TB.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 一种新的，更有效的疫苗对于长期控制结核病显然至关重要。我们认为，在BCG疫苗接种的背景下确定TB保护的相关性以及在寻找未来的抗TB疫苗时使用这些信息至关重要。非人类灵长类动物（NHP）是结核病的出色模型，因为它们与人类的遗传，基因组和生理相似。 NHP发展出类似人类的疾病，具有各种结果，从活跃到慢性疾病到潜在疾病，并显示了人类结核病特征的整个病理特征。六个猕​​猴，在疫苗接种后八个月后，通过支气管镜灌输了1000 CFU，用BCG接种了BCG（丹麦； 50 X 10E6）和一个对照组（盐水），由1000 CFU MTB Erdman挑战。作为该试点项目的一部分，我们从上述所有动物中获得了肺组织，并使用这些组织样品进行全系统的转录组研究。我们比较：i）对照动物的肺部病变中的基因表达与同一动物的非作用组织（NHP肺对MTB感染的反应的转录组比较）； ii）来自同一动物的BCG疫苗接种动物肺部病变中的基因表达（S）（NHP肺对MTB感染的反应中调节的转录组比较）； iii）BCG接种动物的肺部病变中的基因表达对对照动物的肺部病变（对BCG疫苗接种对NHP肺对MTB感染的影响的影响的转录组学评估）。 我们确定了一个小的离散基因基因，其表达因BCG疫苗接种而以统计学意义的方式受到干扰。免疫功能基因，例如在接种和对照组中表达的FOXP3，MIP，IL-6和IL-24，以及IFN-GAMMA，IL-8，IL-8，IL-21BETA，IL-17，IL-17，IL-27和RANTES，仅在BCG疫苗接种动物肺中得到了特异性表达。我们的结果清楚地表明，BCG疫苗接种可清楚有效地调节MTB感染部位的免疫系统。其中一些变化可能在诱导MTB感染的局部保护方面发挥作用。重要的是要在我们的初步研究中表征BCG疫苗接种后观察到的变化，以识别TB保护的关键分子相关性。