Cellular Immunity to Category A-C Viruses in Humans

人类对 A-C 类病毒的细胞免疫

• 批准号: 8243671
• 负责人: Robert William Finberg
• 金额: $ 314.38万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243671
• 关键词: Address; Amino Acids; Antibodies; Antibody Binding Sites; Antibody Formation; Area; Biological Assay; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Cell physiology; Cellular Immunity; Center for Translational Science Activities; Characteristics; Clinical Research; Communities; Core Facility; Cytoprotection; Data; Development; Disease; Dose; Elderly; Endothelial Cells; Epitopes; Extravasation; Flavivirus; Flavivirus Infections; Flow Cytometry; Funding; Goals; Hantavirus; Hemagglutinin; Herpesviridae; Human; Human Herpesvirus 6; Human Virus; Immune response; Immunity; Immunodominant Epitopes; Immunology; Individual; Infection; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza C Virus; Influenza vaccination; Lead; Licensing; Massachusetts; Methods; National Institute of Allergy and Infectious Disease; Nature; Pilot Projects; Plasma; Population; Poxviridae; Process; Production; Proteins; Recommendation; Recording of previous events; Research; Research Personnel; Research Priority; Research Project Grants; Role; Services; Structure; Study Subject; Summary Reports; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Translations; Universities; Vaccination; Vaccines; Variant; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; base; biodefense; career development; cross reactivity; design; high risk; improved; influenza virus vaccine; influenzavirus; innovation; medical schools; mouse model; neutralizing antibody; novel; outreach; pathogen; programs; technology development; tool; viral detection; young adult

DESCRIPTION (provided by applicant): The UMMS Center for Translational Research on Human Immunology and Biodefense (CTRHIB) is a broad-based interdepartmental program to address, as its overall scientific theme, the role of T lymphocytes n the immunopathogenesis of and protection from category A-C viral pathogens in humans. The CTRHIB is a collaborative effort of senior and junior investigators with expertise in human immunology and research on biodefense pathogens, including translation to clinical studies. The UMMS CTRHIB includes 4 Research Projects, a Technology Development Project (TOP), and 5 Cores: Project 1 will analyze human CD4 and CDS T-cell responses to influenza virus vaccine and natural infection and define the characteristics associated with optimal vaccine-induced immune responses. Project 2 will analyze the interactions between innate and adaptive immune responses to virus infection and their effects on endothelial cell function, with a focus on the plasma leakage associated with viral hemorrhagic fevers caused by flaviviruses and hantaviruses. Project 3 will analyze heterologous immunity in flavivirus infections, defining the effects of amino acid variations on cross-reactive T-cell responses in sequential flavivirus infections. Project 4 will analyze the mechanisms underlying the selection of immunodominant epitopes from large DMA viruses, including poxviruses and herpesviruses (HHV-6). The Technology Development Project (TOP) will develop novel methods and tools for epitope discovery, characterization of virus-specific T cells, and high-throughput expansion and detection of virus-specific T cells to facilitate broad application of assays of cellular immunity. Core facilities will provide program administration/educational outreach, pilot projects funding, and centralized services for clinical studies (subject recruitment and characterization), flow cytometry, and production of MHC proteins for use by the research projects and TOP. The CTRHIB addresses important NIAID research priorities related to biodefense pathogens as well as career development for junior investigators. Organizing these activities in a single research Center facilitates cross-departmental and cross-disciplinary interactions, which will be assessed by periodic independent review. RELEVANCE: The UMMS Center for Translational Research in Human Immunology and Biodefense will address key NIAID research priorities through research on human T-cell responses to category A-C viruses (influenza, flaviviruses, hantaviruses, poxviruses, and herpesviruses) and development of new tools for analysis of human virus-specific T cells. The Center provides centralized services and coordination for the research. PROJECT 1: Human CD8+ and CD4+ T Cells Responses to Influenza Infection and Vaccination (TERAJIMA, M) PROJECT 1 DESCRIPTION (provided by applicant): The overall goal of this project is to define the human T-cell responses to influenza infection and to trivalent inactivated influenza vaccines (TIV) in younger and older adults. We hypothesize that (1) human T-cell responses in younger adults will be greater than those in older adults to vaccination and to infection, (2) human CD4+ and CD8+ T-cell responses will be lower to vaccine than to infection and (3) the TlV-induced T-cell responses will correlate with the amount of internal proteins in the individual licensed vaccines. Influenza A virus hemagglutinin (HA) is a target of protective neutralizing antibodies, which are subtypespecific and vulnerable to antigenic drift. CD4+ and CD8+ T-cell responses are thought to be more subtype cross-reactive. It is clear from studies in mouse models of influenza A virus infections that T cells can provide a second important line of defense, especially in the face of marked antigenic drift or shift due to emergence of viruses with changes in HA antibody combining sites, and there are also limited clinical studies which suggest the importance of T cells for protection, especially in a high-risk elderly population. There is, however, only a limited amount of data available on human T-cell responses to influenza infection or vaccination. Importantly there appears to be more subtype cross-reactivity among influenza A virus T cell epitopes than to the antibody epitopes on HA. At present limited data suggest that current TIVs induce low to moderate CD4+ and CD8+ T-cell responses. However, we found some individuals with high T-cell responses to TIV. Recently, we and the other group also found the amount of influenza internal proteins in the TIVs differs. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about TIVs induction of T-cell responses and nothing is known about their contribution to vaccine associated protection. In Aim 1 we propose to analyze CD4+ and CD8+ T-cell responses to TIV vaccination in younger and older adults. In these studies, we will also compare the three US-licensed TIVs for their ability to stimulate CD4+ and CD8+ T-cell responses and for protection (in older adults). In Aim 2 we propose to characterize CD4+ and CD8+ T-cell responses to natural influenza infections in younger and older adults and compare them to the CD4+ and CD8+ T-cell responses induced by TIV. These analyses may lead to approaches towards improved influenza vaccines, which can protect against new and emerging influenza virus infections including H5N1 and other non-human strains. RELEVANCE: For efficient protection against influenza A virus infection, influenza vaccines need to induce cellular immune responses as well as neutralizing antibody responses, especially in older adults. Despite the recommendation and use of about 100 million vaccine doses per year in the US alone, very little is known about cellular immune responses induced by the vaccines and nothing is known about their contribution to protection, which we propose to study in younger and older adults to help design better influenza vaccines.

描述（由申请人提供）：umms人类免疫学和生物幻想转化研究中心（CTRHIB）是一个基于广泛的部门间计划，旨在解决其整体科学主题，是T淋巴细胞的作用，n t ymphocytes n n t ymphocytes n n t y n ymphocytes n n t y n ymphocyte n n t rymphocytes n n t rymphocytip n n t rymphocyte n n an ansans n of themans n of Specory A-C-C病毒性病原体的保护和保护。 CTRHIB是高级和初级研究人员的合作努力，该研究人员在人类免疫学和生物反素病原体研究方面具有专业知识，包括转化为临床研究。 UMMS CTRHIB包括4个研究项目，一个技术开发项目（TOP）和5个核心：项目1将分析人类CD4和CDS T细胞对流感病毒疫苗和自然感染的反应，并定义与最佳疫苗诱导的免疫反应相关的特征。项目2将分析对病毒感染的先天和适应性免疫反应及其对内皮细胞功能的影响之间的相互作用，重点是与黄素和hantavires引起的病毒出血狂热相关的血浆泄漏。项目3将分析黄病毒感染中的异源免疫力，从而定义氨基酸变异对顺序黄病毒感染中交叉反应性T细胞反应的影响。项目4将分析从大型DMA病毒（包括痘病毒和疱疹病毒）（HHV-6）中选择免疫主流表位的基础机制（HHV-6）。技术开发项目（TOP）将开发新的方法和工具，用于发现表位，病毒特异性T细胞的表征以及高通量扩张以及病毒特异性T细胞的检测，以促进细胞免疫测定法的广泛应用。核心设施将为临床研究（受试者招聘和表征），流式细胞仪以及MHC蛋白的生产提供计划管理/教育外展，试点项目资金和集中式服务，以供研究项目和TOP使用。 CTRHIB探讨了与生物防腐病原体有关的重要NIAID研究重点以及初级研究人员的职业发展。在单个研究中心组织这些活动促进了跨部门和跨学科的互动，这将通过定期独立审查评估。 相关性：人类免疫学和生物探讨的UMM转化研究中心将通过对人类T细胞对A-C病毒（流感，黄素病毒，Hantaviruess，poxviruses，Poxviruses和Herpesviruse）的T细胞反应的研究来解决关键的NIAID研究优先级，并通过分析人类病毒特异性T细胞的新工具的开发。该中心为研究提供集中服务和协调。 项目1：人类CD8+和CD4+ T细胞对流感感染和疫苗接种的反应（Terajima，M） 项目1描述（由申请人提供）：该项目的总体目标是定义人类对流感感染的反应，并在年轻人和老年人中定义了对流感感染的人类T细胞的反应和三价失活的流感疫苗（TIV）。我们假设（1）年轻人中的人类T细胞反应将大于老年人对疫苗接种和感染的反应，（2）人类CD4+和CD8+ T-Cell反应对感染的疫苗比感染要低，并且（3）TLV诱导的T细胞反应将与个人持有量的内部蛋白质相关。流感病毒血凝素（HA）是保护性中和抗体的靶标，该抗体是亚型亚型且容易受到抗原漂移的影响。 CD4+和CD8+ T细胞响应被认为更亚型交叉反应。从对流感A的小鼠模型的病毒感染的研究可以清楚地看出，T细胞可以提供第二种重要的防御线，尤其是由于病毒的出现而引起的明显的抗原漂移或转移，与HA抗体结合部位的变化有关，并且也存在有限的临床研究，并且表明T细胞的重要性在PARTING上的重要性，尤其是在高风险的高危老年人中。但是，关于人类T细胞对流感感染或疫苗接种的人类T细胞反应的可用数据有限。重要的是，在HA上，流感病毒T细胞表位的亚型交叉反应似乎更多的亚型交叉反应性。目前，有限的数据表明，当前的TIV诱导低至中度的CD4+和CD8+ T细胞响应。但是，我们发现一些对TIV的T细胞反应高的人。最近，我们和另一组也发现TIV中的流感内部蛋白质的量有所不同。尽管仅在美国就建议和使用约1亿次疫苗剂量，但对于TIV诱导T细胞反应的启发知之甚少，对它们对疫苗相关保护的贡献一无所知。在AIM 1中，我们建议分析年轻和老年人对TIV疫苗接种的CD4+和CD8+ T细胞反应。在这些研究中，我们还将比较三个由美国许可的TIV刺激CD4+和CD8+ T细胞反应和保护（在老年人中）的能力。在AIM 2中，我们建议表征CD4+和CD8+ T细胞对年轻和老年人自然流感感染的反应，并将其与TIV引起的CD4+和CD8+ T细胞反应进行比较。这些分析可能导致改善流感疫苗的方法，这些方法可以预防新的和新兴的流感病毒感染，包括H5N1和其他非人类菌株。 相关性：为了有效保护流感病毒感染，流感疫苗需要诱导细胞免疫反应以及中和抗体反应，尤其是在老年人中。尽管仅在美国就建议和使用约1亿次疫苗剂量，但对疫苗引起的细胞免疫反应知之甚少，并且对它们对保护的贡献一无所知，我们建议在年轻和老年人中研究它们，以帮助设计更好的流感疫苗。