Profiling of influenza-specific immune responses in the elderly

描述(由申请人提供)：了解控制病毒反应的免疫机制的核心是更全面地了解抗原特异性免疫反应的深度和广度。这对于理解为什么在老年人群中对感染的易感性增加，而在年轻人群中具有保护性的疫苗策略的效力较低，这一点将特别重要。为了研究这一点，我们建议应用一种新型的高通量、基于芯片的细胞微阵列来表征感染/疫苗接种期间的人类免疫反应。细胞微阵列是一项新兴的技术，在医学诊断、疫苗开发、自身免疫性疾病的治疗以及检测潜在的生物恐怖分子方面具有广阔的应用前景。在R21的应用中，我们将特别关注流感，因为流感感染继续在高发病率和高死亡率方面产生重大的社会影响，特别是在老年人中。具体地说，在目标1中，我们建议展示多肽负载的HLA-Ig芯片在体外扩增的CTL中检测免疫显性和亚显性流感特异性免疫反应的有效性。一旦产生并在体外扩增的细胞上进行测试，我们将分析接种疫苗的志愿者和有流感感染记录的患者的反应。这将在老年和年轻的队列中进行，以确定在反应CTL人群中看到的差异。虽然在这一初步应用中，重点将放在HLAA2对流感的反应上，但我们计划在应用的第二阶段将这里建议的工作扩大到涵盖其他HLAI和II类等位基因以及更广泛的其他传染病。

Description (provided by applicant): Central to understanding immune mechanisms that control viral responses is a more comprehensive understanding of the depth and breadth of antigen-specific immune responses. This will be particularly important in understanding why in the elderly population there is increased susceptibility to infection and less efficacy in vaccine strategies that are protective in younger cohorts. To study this we propose to apply a novel high-throughput, chip-based cellular microarray to characterize human immune responses during infections/vaccinations. Cellular microarrays are an emerging technology with promising applications in medical diagnostics, vaccine development, treatment of autoimmune diseases, and detection of potential agents of bioterrorism. In this R21 application we will focus specifically on influenza as influenza infections continue to have a major societal impact in terms of high morbidity and mortality, especially in the elderly. Specifically in Aim 1 we propose to demonstrate the efficacy of peptide-loaded HLA-Ig chips to examine both immunodominant and subdominant influenza specific immune responses in CTL expanded in vitro. Once generated and tested on the in vitro expanded cells we will analyze responses from vaccinated volunteers and patients who have documented influenza infection. This will be done for both elderly and younger cohorts to determine differences seen in responding CTL populations. While in this preliminary application the focus will be on the HLA A2 response to influenza, we plan to expand the work proposed here to cover other HLA class I and II alleles as well as other infectious diseases more broadly in the second U01 phase of the application.