T cell responses at the site of infection

感染部位的 T 细胞反应

• 批准号: 9089889
• 负责人: GEORG Michael LAUER
• 金额: $ 21.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089889
• 关键词: Acute; Address; Area; Biological; Blood; CD8B1 gene; Cell Count; Cell Differentiation process; Cell physiology; Cells; Chronic; Clinical; Complex; Development; Dimensions; Event; Failure; Fine needle aspiration biopsy; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; HIV; HIV/HCV; Health; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Heterogeneity; High Prevalence; Human; Immune; Immune response; Immunity; Immunotherapy; Individual; Infection; Infection Control; Intervention; Investigation; Liver; Lymphocyte; Memory; Operative Surgical Procedures; Organ; Outcome; Pattern; Pharmacotherapy; Population; Prevention; Prospective Studies; Risk; Sampling; Site; System; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Tissues; Transcriptional Regulation; Vaccines; Viral; Viremia; Virus; Virus Diseases; cancer immunotherapy; design; exhaust; exhaustion; high risk; human tissue; improved; insight; interest; intrahepatic; man; minimally invasive; novel; novel strategies; novel therapeutics; prophylactic; response

 DESCRIPTION (provided by applicant): The difficulties in generating effective T-cell based vaccines and immunotherapies against chronic infections with viruses such as HCV and HIV highlight our limited understanding of what defines a successful versus an inadequate T cell response. Studies in human infection will be critical to better guide new approaches for inducing or improving T cell responses and recent technological advances give opportunity to overcome previous boundaries in assessing the T cell response. One important and understudied aspect of the T cell response is that T cells at the site of infection are and have to be qualitatively different from those circulating in the blood. For obvious reasons, studies on human tissue-resident T cells are limited to material either removed for clinical indications or very small tisse samples that can be removed without significant risk for the individual. The challenge is to obtain material that allows meaningful comparisons and to generate complex information from typically very small numbers of cells that are available for analysis. HCV infection is one of the most common chronic viral infections in man and has two key features that make it an excellent system for studies of immune protection and immune failure in humans: 1) HCV infection can be both chronic and self-limiting and 2) tissue from HCV+ individuals can be routinely obtained through surgery, biopsies and fine needle aspiration. We will utilize these two key features of HCV infection in conjunction with novel approaches for analyzing small numbers of cells of interest to define critical features of T-cells directly from the site of infection that do and do ot control the virus. Our hypothesis is that in chronic infection T cells with specific signatures of dysfunction, exhaustion and dysregulation will enrich in the liver, whereas in resolved infection fully formed memory T cells with be detectable in blood and liver. In aim 1 we will use multiplex gene expression analysis to compare HCV-specific T cells in chronic and resolved infection, using cells from both the liver and the blood. Aim 2 will significantly increase the potential scop of the analytical approach established in aim 1 by adapting it for material from fine needle aspirations. These can be performed electively in well-defined clinical situations, allowing to extend the study of intrahepatic T cells to subjects with acute infection or other clinical timepoints of immunological interest in which so far only T cells from the blood have been analyzed. With completion of the studies proposed in this exploratory/developmental application we will have gained novel insights into critical aspects of protective immunity and immune failure in humans and will also have laid the foundation for prospective studies of immunological perturbations in humans.

 描述（由申请人提供）：在产生有效的基于T细胞的疫苗和免疫疗法以对抗病毒（如HCV和HIV）的慢性感染方面的困难突出了我们对成功与不充分T细胞应答的定义的有限理解。人类感染研究对于更好地指导诱导或改善T细胞反应的新方法至关重要，最近的技术进步为克服之前评估T细胞反应的界限提供了机会。 T细胞反应的一个重要和未充分研究的方面是，感染部位的T细胞与血液中循环的T细胞在性质上是不同的。由于显而易见的原因，对人类组织驻留T细胞的研究仅限于因临床适应症而取出的材料或可以在对个体没有重大风险的情况下取出的非常小的组织样本。挑战在于获得允许有意义的比较的材料，并从通常非常少量的可用于分析的细胞中产生复杂的信息。HCV感染是人类最常见的慢性病毒感染之一，具有两个关键特征，使其成为研究人类免疫保护和免疫失败的优秀系统：1）HCV感染可以是慢性和自限性的，2）来自HCV+个体的组织可以通过手术、活检和细针抽吸常规获得。 我们将利用HCV感染的这两个关键特征，结合分析少量感兴趣细胞的新方法，直接从感染部位确定T细胞的关键特征，这些特征可以控制病毒，也可以不控制病毒。我们的假设是，在慢性感染中，具有功能障碍、衰竭和失调的特异性特征的T细胞将在肝脏中富集，而在消退的感染中，完全形成的记忆T细胞在血液和肝脏中可检测到。在目标1中，我们将使用多重基因表达分析来比较慢性感染和消退感染中的HCV特异性T细胞，使用来自肝脏和血液的细胞。目标2将显著增加目标1中建立的分析方法的潜在范围，使其适用于来自细针抽吸的材料。这些可以在明确定义的临床情况下选择性地进行，允许将肝内T细胞的研究扩展到患有急性感染或其他免疫学关注的临床时间点的受试者，其中迄今为止仅分析了来自血液的T细胞。 随着这项探索性/开发性应用中提出的研究的完成，我们将获得对人类保护性免疫和免疫失败关键方面的新见解，并将为人类免疫扰动的前瞻性研究奠定基础。