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 人类免疫学和生物防御转化研究中心 (CTRHIB) 是一个基础广泛的跨部门项目，其总体科学主题是解决 T 淋巴细胞在免疫发病机制和免受类别保护中的作用。人类中的 A-C 病毒病原体。 CTRHIB 是高级和初级研究人员的共同努力，他们拥有人类免疫学和生物防御病原体研究方面的专业知识，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免疫相关的特征回应。项目2将分析对病毒感染的先天免疫反应和适应性免疫反应之间的相互作用及其对内皮细胞功能的影响，重点关注与黄病毒和汉坦病毒引起的病毒性出血热相关的血浆渗漏。项目 3 将分析黄病毒感染中的异源免疫，确定氨基酸变异对连续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)）中选择免疫显性表位的机制。技术开发项目 (TOP) 将开发新的方法和工具，用于表位发现、病毒特异性 T 细胞的表征以及病毒特异性 T 细胞的高通量扩增和检测，以促进细胞免疫测定的广泛应用。核心设施将提供项目管理/教育推广、试点项目资助以及临床研究（受试者招募和表征）、流式细胞术以及供研究项目和 TOP 使用的 MHC 蛋白生产的集中服务。 CTRHIB 致力于解决与生物防御病原体相关的 NIAID 重要研究重点以及初级研究人员的职业发展。在一个研究中心组织这些活动有助于跨部门和跨学科的互动，并将通过定期独立审查进行评估。 相关性：UMMS 人类免疫学和生物防御转化研究中心将通过研究人类 T 细胞对 A-C 类病毒（流感、黄病毒、汉坦病毒、痘病毒和疱疹病毒）的反应以及开发新的分析工具来解决 NIAID 的关键研究重点人类病毒特异性T细胞。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确定年轻人和老年人中人类 T 细胞对流感感染和三价灭活流感疫苗 (TIV) 的反应。我们假设 (1) 年轻人的人类 T 细胞对疫苗接种和感染的反应将大于老年人，(2) 人类 CD4+ 和 CD8+ T 细胞对疫苗的反应将低于对感染的反应，并且 (3 ) TIV 诱导的 T 细胞反应将与各个许可疫苗中的内部蛋白质含量相关。甲型流感病毒血凝素 (HA) 是保护性中和抗体的目标，该抗体具有亚型特异性，容易受到抗原漂移的影响。 CD4+ 和 CD8+ T 细胞反应被认为更具亚型交叉反应性。从甲型流感病毒感染小鼠模型的研究中可以清楚地看出，T 细胞可以提供第二道重要的防线，特别是在面对由于 HA 抗体结合位点发生变化的病毒出现而导致的明显抗原漂移或转移时，T 细胞可以提供第二道重要的防线。也有有限的临床研究表明 T 细胞对于保护的重要性，特别是在高危老年人群中。然而，关于人类 T 细胞对流感感染或疫苗接种反应的数据有限。重要的是，甲型流感病毒 T 细胞表位之间似乎比 HA 上的抗体表位有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 细胞反应。然而，我们发现一些个体对 TIV 的 T 细胞反应较高。最近，我们和另一组还发现 TIV 中流感内部蛋白的含量不同。尽管仅在美国每年就建议和使用约 1 亿剂疫苗，但人们对 TIV 诱导 T 细胞反应知之甚少，也对其对疫苗相关保护的贡献一无所知。在目标 1 中，我们建议分析年轻人和老年人中 CD4+ 和 CD8+ T 细胞对 TIV 疫苗接种的反应。在这些研究中，我们还将比较三种美国许可的 TIV 刺激 CD4+ 和 CD8+ T 细胞反应和保护（老年人）的能力。在目标 2 中，我们建议表征年轻人和老年人对自然流感感染的 CD4+ 和 CD8+ T 细胞反应，并将其与 TIV 诱导的 CD4+ 和 CD8+ T 细胞反应进行比较。这些分析可能会导致改进流感疫苗的方法，这种疫苗可以预防新出现的流感病毒感染，包括 H5N1 和其他非人类毒株。 相关性：为了有效预防甲型流感病毒感染，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。尽管仅在美国每年就建议和使用约 1 亿剂疫苗，但人们对疫苗引起的细胞免疫反应知之甚少，也对其对保护的贡献一无所知，我们建议在年轻人和老年人中进行研究帮助设计更好的流感疫苗。