Cellular Immunity to Category A-C Viruses in Humans

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T淋巴细胞在人类a - c类病毒病原体的免疫发病机制和保护中的作用。CTRHIB是由具有人类免疫学和生物防御病原体研究专长的高级和初级研究人员共同努力的结果，包括转化为临床研究。UMMS CTRHIB包括4个研究项目、1个技术开发项目（TOP）和5个核心项目：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，并确定与最佳疫苗诱导免疫反应相关的特征。项目2将分析病毒感染的先天免疫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，重点研究黄病毒和汉坦病毒引起的病毒性出血热引起的血浆渗漏。项目3将分析黄病毒感染中的异源免疫，确定序列黄病毒感染中氨基酸变化对交叉反应性t细胞反应的影响。项目4将分析大型DMA病毒（包括痘病毒和疱疹病毒（HHV-6））免疫显性表位选择的机制。技术开发项目（TOP）将开发新的方法和工具，用于发现表位，表征病毒特异性T细胞，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、临床研究（受试者招募和表征）、流式细胞术和MHC蛋白生产的集中服务，供研究项目和TOP使用。CTRHIB解决了与生物防御病原体相关的重要NIAID研究重点以及初级研究人员的职业发展。在一个单独的研究中心组织这些活动有助于跨部门和跨学科的互动，这将通过定期独立审查进行评估。

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.