CD4+ T and B cell mechanisms of influenza vaccine non-responsiveness in older adu

描述(申请人提供)：根据疾控中心的数据，每年有超过2万人死于流感，20万人住院，其中90%是65岁以上的人。接种季节性三价灭活流感疫苗仍然是疾控中心建议的主要公共卫生措施；然而，这种疫苗在最需要保护的老年人口中的效力显著降低，往往低于50%。因此，迫切需要更好地了解免疫和疫苗接种失败的情况，以制定更好的战略，减少老年人流感相关的发病率和死亡率。在组织层面上，老年人接种疫苗失败的潜在机制--对流感疫苗的免疫无反应--仍有待确定。大多数对疫苗接种的关键免疫反应发生在区域引流淋巴结(LN)，而不是外周血。有鉴于此，这项建议的中心新颖性和创新点是明确区域引流层内潜在的B和T细胞属性，这些属性可以解释老年人免疫无应答和疫苗接种失败的原因。在这里，我们建议直接检查接种后获得的近端LN活检组织中流感疫苗诱导的CD4+T和B细胞。最近在小鼠身上的研究发现，T滤泡辅助细胞(TFH)在免疫后LN生发中心的发育中起关键作用，以提供最佳的B淋巴细胞刺激，以利用高亲和力抗体发展持久的体液免疫。我们的初步数据表明，血液中的TFH细胞随着年龄的增长而下降，但对于对流感疫苗无效的老年人来说更是如此。因此，我们假设在老年人接种流感疫苗后，T滤泡辅助细胞(TFH)和辅助性T细胞1型(Th1)转录编程、水平、表型和功能的缺陷导致抗体数量和质量的减少，临床上转化为无应答和疫苗失败。此外，我们假设这些缺陷将在老年疫苗无效者中最为明显，并有助于在老年人中观察到免疫衰弱表型。我们将在以下具体目标中解决这些假设：目标1：确定接种前LN和血液中总的和流感特异性的CD4+Th1/Tfh亚群和B细胞的基线差异是否预测旧的流感疫苗失败/无应答(NR)和旧的疫苗应答(R)。目的：确定流感疫苗接种后，局部淋巴组织和血液中的CD4+Th1/Tfh细胞和B细胞应答的特异性缺陷，从而导致旧流感疫苗的NR和R表型。

DESCRIPTION (provided by applicant): According to the CDC, there are over 20,000 deaths and 200,000 hospitalizations due to influenza each year, 90% of which were in people over age 65. The administration of the seasonal trivalent inactivated influenza vaccine remains the primary public health measure recommended by the CDC; however, this vaccine has significantly reduced efficacy, often below 50%, in this older population that needs protection most. Thus, a better understanding of immunologic and vaccination failure is urgently needed to develop better strategies to reduce influenza-related morbidity and mortality in older adults. At the tissue level, the underlying mechanisms of vaccine failure--immunologic non-responsiveness to influenza vaccination--in older adults remain to be defined. Most key immunologic responses to vaccination occur within regional draining lymph nodes (LN), not the peripheral blood. In light of this, the central novelty and innovation of this proposal is to defin the underlying B and T cell properties within the regional draining LN that can account for immunologic non- responsiveness and vaccination failure in older adults. Here we propose direct examination of influenza vaccine-induced CD4+ T and B cells within proximal LN biopsies obtained after vaccination. Recent studies in mice have identified T follicular helper (Tfh) cells key role in the development of the germinal center in the LN after vaccination to provide optimal stimulation of B lymphocytes for the development of long lasting humoral immunity with high affinity antibodies. Our preliminary data suggest that Tfh cells in blood decline with aging, but more-so for the subset of older adults who fail to respond to influenza vaccine. As such, we hypothesize that defects in T follicular helper cell (Tfh) and T helper type 1 (Th1) transcription programming, levels, phenotype, and function result in reduced antibody quantity and quality after influenza vaccination in older adults, clinically translating to non- responsiveness and vaccine failure. Moreover, we hypothesize that these defects will be most pronounced in older vaccine non-responders and contribute to the immunosenescent phenotype observed in older persons. We will address these hypotheses in the following Specific Aims: Aim 1: To determine if baseline differences in total and flu-specific CD4+ Th1/Tfh subsets and B cells in LN and blood prior to vaccination predict old influenza vaccine failures/non-responders (NR) and old vaccine-responders (R). Aim 2: To determine the specific defects in the induction of CD4+ Th1/Tfh cell and B cell responses in regional LN and blood acutely after influenza vaccination that result in the old influenza vaccine NR and R phenotypes.