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

描述（由申请人提供）：根据美国疾病控制与预防中心的数据，每年有超过2万人因流感死亡，20万人因流感住院，其中90%的人年龄在65岁以上。接种季节性三价灭活流感疫苗仍然是疾病预防控制中心建议的主要公共卫生措施；然而，在最需要保护的老年人群中，这种疫苗的效力显著降低，通常低于50%。因此，迫切需要更好地了解免疫和疫苗接种失败，以制定更好的策略来降低老年人流感相关的发病率和死亡率。在组织水平上，疫苗失败的潜在机制——对流感疫苗免疫无反应——在老年人中仍有待确定。大多数关键免疫应答疫苗发生在区域引流淋巴结（LN），而不是外周血。鉴于此，该建议的核心新颖性和创新之处在于定义了区域引流LN内潜在的B细胞和T细胞特性，这些特性可以解释老年人的免疫无反应性和疫苗接种失败。在这里，我们建议在疫苗接种后获得的近端淋巴结活检中直接检查流感疫苗诱导的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）在接种疫苗后LN生发中心的发育中起关键作用，为B淋巴细胞提供最佳刺激，形成持久的具有高亲和力抗体的体液免疫。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，但对于那些对流感疫苗没有反应的老年人来说，这种情况更为严重。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T辅助型1 （Th1）转录编程、水平、表型和功能的缺陷导致抗体数量和质量降低，在临床上转化为无反应性和疫苗失败。此外，我们假设这些缺陷将在年龄较大的疫苗无应答者中最为明显，并有助于在老年人中观察到的免疫衰老表型。我们将在以下具体目的中解决这些假设：目的1：确定接种前LN和血液中总CD4+ Th1/Tfh亚群和B细胞的基线差异是否预测旧流感疫苗失败/无反应（NR）和旧疫苗反应(R)。目的2：确定流感疫苗接种后急性区域LN和血液中诱导CD4+ Th1/Tfh细胞和B细胞反应的特异性缺陷，导致旧流感疫苗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.