Induction of regulatory T cells by highly virulent isolates of M.tuberculosis

高毒力结核分枝杆菌分离株诱导调节性 T 细胞

• 批准号: 7896347
• 负责人: Diane Joyce Ordway
• 金额: $ 18.38万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896347
• 关键词: Adoptive Cell Transfers; Aerosols; Animals; Biological; Bone Marrow; CD4 Positive T Lymphocytes; Cause of Death; Cavia; Cell Wall; Cells; Clinical; Data; Dose; Family; Generations; Genomics; IL2RA gene; Immune response; Immunity; Individual; Infection; Inflammation; Inflammatory; Interleukin-10; Kinetics; Laboratories; Lipids; Lung; Lung Inflammation; Modeling; Modification; Morbidity - disease rate; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Organism; Pathology; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Process; Property; Reagent; Regulatory T-Lymphocyte; System; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Transgenic Mice; Tuberculosis; Virulence; Virulent; Work; base; chemotherapy; clinically relevant; design; innovation; mortality; novel vaccines; public health relevance; response

DESCRIPTION (provided by applicant): This application proposes the simple hypothesis that highly virulent clinical isolates of Mycobacterium tuberculosis, associated as they are with severe inflammation and lung damage, are far more likely as a result to induce regulatory T cell subsets compared to strains of relatively lower virulence. To test this hypothesis we have selected six clinically relevant isolates of an increasing range of virulence. We will use newly developed techniques to follow their emergence, influx, and positioning in the lungs of mice infected by a low dose aerosol with these isolates, use new processes to specifically ablate them, and perform cell transfer studies to directly examine their effects on TH1 immunity. Not only should these studies reveal some basic information regarding the conditions under which regulatory T cells are induced, but they have the potential to provide fundamental information relevant to issues such as the efficacy of new vaccines against clinical strains that acquire high levels of such T cells, and the status of subsequent immunity in individuals infected with highly virulent strains who have successfully been treated with chemotherapy. This then forms the basis of this R21 application. Is the induction of regulatory T cells restricted to this particular strain or is it a more general clinical phenomenon? If just a facet of HN878, is this due to its possession of an unusual cell wall lipid? Is it a specific property of the highly transmitted W-Beijing family? Do such cells directly inhibit effector T cells, or are they designed to reduce inflammation? Efforts are now underway to genomically sequence multiple clinical strains, and we hope to include these strains to be used here in a newly formed sequencing Consortium. As yet, nobody actually knows why certain strains of TB are "virulent" and others less so, and it will require a combination of genomic information compared to basic biological information to try to uncover this. One aspect of virulence could be the ability of the organism to subvert immunity, as we hypothesize here. We aim to determine the kinetics of generation of regulatory T cells in mice infected with a representative panel of clinical isolates of M.tuberculosis, in comparison to effector T cell subsets. We will also track and deplete regulatory T cells in GFP-Foxp3+ and transgenic mice, and further characterize their function in an innovative new adoptive cell transfer system. PUBLIC HEALTH RELEVANCE: Over the past decade the number of isolates of M.tuberculosis that are multi-drug resistant has risen alarmingly. Many of these isolates are from the Beijing/W family which stand out due to the considerable morbidity and mortality they cause worldwide. The basis of this R21 proposal is to characterize if M.tuberculosis strains of extremely high virulence interacted differently with the innate and/or acquired specific host response compared to other strains.

描述（由申请人提供）：本申请提出了这样一个简单的假设，即结核分枝杆菌的高毒性临床分离株与严重的炎症和肺损伤相关，因此与相对较低的毒力菌株相比，诱导调节性T细胞亚群的可能性更大。为了检验这一假设，我们选择了六种与毒力范围增加的临床相关分离株。我们将使用新开发的技术遵循它们的出现，涌入和定位在被低剂量气溶胶感染的小鼠的肺中，并使用这些分离株，使用新过程来具体消融它们，并进行细胞转移研究以直接检查其对TH1免疫的影响。这些研究不仅应该揭示有关诱导调节性T细胞的条件的一些基本信息，而且它们有可能提供与问题有关的基本信息，例如新疫苗对临床菌株的疗效，这些临床菌株获得了高水平的T细胞，以及在受到高度毒性菌株感染的患者中随后的免疫力的状态，这些菌株已成功地接受了化学治疗。然后，这构成了此R21应用程序的基础。调节T细胞的诱导是否仅限于这种特定菌株，还是更通用的临床现象？如果只是HN878的一个方面，这是否是由于它拥有不寻常的细胞壁脂质吗？它是高度传播的W-Beijing家族的特定财产吗？这样的细胞会直接抑制效应T细胞，还是为减少炎症而设计？现在正在进行基因组序列多种临床菌株的努力，我们希望将这些菌株包括在新形成的测序联盟中。到目前为止，没有人真正知道为什么某些结核病是“有毒的”，而其他菌株则较少如此，并且与基本的生物学信息相比，它将需要结合基因组信息，以试图发现这一点。正如我们在这里假设的那样，毒力的一个方面可能是生物体颠覆免疫力的能力。我们旨在确定与效应T细胞亚群相比，感染了由大肠杆菌临床分离株的代表性临床分离株感染的小鼠的调节T细胞的动力学。我们还将跟踪和耗尽GFP-FOXP3+和转基因小鼠中的调节性T细胞，并进一步表征它们在创新的新收养细胞转移系统中的功能。 公共卫生相关性：在过去的十年中，多药抗药性的大结核病分离株数量令人震惊。这些分离株中的许多来自北京/W家族，由于它们在全球范围内引起的大量发病率和死亡率而脱颖而出。该R21提案的基础是表征与其他菌株相比，毒力极高的杂交菌株与先天和/或获得的特定宿主反应的相互作用不同。