T cell responses to H1N1 and a longitudinal study of seasonal flu vaccination

T 细胞对 H1N1 的反应和季节性流感疫苗接种的纵向研究

• 批准号: 8377319
• 负责人: Mark Morris Davis
• 金额: $ 23.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8377319
• 关键词: 3 year old; Age; Antibody Formation; Antigens; B-Lymphocytes; Biological Assay; Biostatistics Core; CD8B1 gene; Cells; Communicable Diseases; Disease Outbreaks; Epitopes; Exposure to; Failure; Gene Expression; Genetic Identity; Genomics; Genotype; Haplotypes; Health; Human; Human Volunteers; Immune; Immune response; Immune system; Immunologic Markers; Immunologic Monitoring; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Interleukin-17; Longitudinal Studies; Measures; Pattern; Peptide/MHC Complex; Play; Production; Role; Serum; Severity of illness; Shapes; System; Systems Biology; T cell response; T-Lymphocyte; Twin Studies; Vaccination; Vaccine Design; Vaccines; Variant; cohort; combinatorial; cytokine; granzyme B; immune function; neutralizing antibody; novel; novel marker; pandemic influenza; response; seasonal influenza; senescence; young adult

Here we propose to characterize the responses of CD4[+], CD8[+] and gamma-delta T cells to the pandemic influenza H1N1v vaccination or infection in human volunteers. We will use both systems biology approaches as well as analyzing a variety of antigen specific responses with combinatorial peptide-MHC tetramers combined with single cell cytokine analysis, in which we can screen for hundreds of different epitopes and dozens of cytokines. In Aim 1. we will ask whether particular epitope or cytokine expression patterns correlate with a robust vaccine response, as measured by a microneutralization assay, and/or a granzyme B T cell assay, or in the case of infected individuals, disease severity. With the twin studies we will ask how closely does dominant epitope choice follow genetic identity and does that change with increasing age and exposure to infectious diseases. This will be complementary to the results obtained with the complete HLA genotyping being done by the Genomics Core, as we expect that HLA haplotypes will have a major influence on epitope selection and dominance. In Aim 2. we will characterize activation markers and cytokine expression in gamma-delta T cells, which recent evidence suggests influence antibody responses and help shape the responses of CD4[+] and CD8[+] T cells and other immune system components through the early production of IL-17. In Aim 3 we will continue our now three year old longitudinal study of seasonal flu vaccination in young adults (20-30 yrs.) versus older cohorts (60-96 yrs), taking a systems biology approach with the help ofthe Human Immune Monitoring Core and the Biostatistics Core in which we correlate gene expression, cytokine stimulation and serum cytokines with parameters such as immune senescence to uncover new markers and mechanisms behind the failure of proper immune function in many older people. We have already identified a number of new markers of immune deficiency, including a decrease in AID expression in B cells and deficient responses to cytokines in many older people using phosphoflow analysis. Support by this mechanism will allow us to look extensively at year-on-year variations and early markers of immune senescence. Lastly, this same systems approach will be taken to compare H1N1v vaccination responses to actual infections, which should help us to understand the similarities and differences between the two and aid in the design of vaccines that are more protective.

在这里，我们建议表征人类志愿者中CD4 [+]，CD8 [+]和伽马 - 戴尔塔T细胞对大流行性流感H1N1V疫苗接种或感染的反应。我们将使用两种系统生物学方法，并使用组合肽-MHC四聚体以及单细胞因子分析来分析各种抗原特异性反应，在其中，我们可以筛选数百种不同的表位和数十个细胞因子。在AIM 1中。我们将询问特定的表位或细胞因子表达模式与通过微中性化测定法和/或颗粒酶B T细胞测定法测量的良好疫苗反应相关，或者在感染个体的情况下，疾病严重程度。通过双胞胎研究，我们将询问主要的表位选择遵循遗传认同的距离，并随着年龄的增长和暴露于传染病的影响而改变。这将与基因组核心完成的完整HLA基因分型获得的结果互补，因为我们预计HLA单倍型将对表位选择和优势产生重大影响。在AIM 2中。我们将表征γ-二甲状腺T细胞中的激活标记和细胞因子的表达，最近的证据表明，通过IL-17的早期生产来影响抗体反应，并有助于塑造CD4 [+]和CD8 [+] T细胞以及其他免疫系统成分的反应。在目标3中，我们将继续我们现在三岁的年轻人（20 - 30年）对季节性流感疫苗接种的纵向研究（20 - 30年）与较旧的队列（60 - 96年）（60 - 96年），在人类免疫监测核心的帮助下采用了系统生物学方法，并与基因表达和疾病相关，并将其与之相关，并将其与疾病的疾病相关联，并将其与疾病的疾病相关。许多老年人的适当免疫功能失败背后的机制。我们已经确定了许多免疫缺陷的新标记，包括使用磷光流分析的许多老年人中B细胞的辅助表达降低以及对细胞因子的不足反应。通过这种机制的支持将使我们能够广泛地研究同比的变化和免疫衰老的早期标记。最后，将采用相同的系统方法比较H1N1V疫苗接种对实际感染的反应，这应该有助于我们了解两者之间的相似性和差异，并有助于设计更具保护性的疫苗。