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

老年人流感疫苗无反应的 CD4 T 和 B 细胞机制

• 批准号: 8985652
• 负责人: Michael R Betts
• 金额: $ 45.49万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8985652
• 关键词: Accounting; Address; Aging; Antibodies; Antibody Affinity; Avidity; B-Lymphocyte Subsets; B-Lymphocytes; Biopsy; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Data; Defect; Development; Elderly; Failure; Frequencies; Genetic Transcription; Health; Helper-Inducer T-Lymphocyte; Hemagglutinin; Hospitalization; Human; Humoral Immunities; Immune; Immune response; Immunoglobulin Somatic Hypermutation; Immunologics; Individual; Influenza; Influenza vaccination; Light; Measures; Memory B-Lymphocyte; Morbidity - disease rate; Mus; Older Population; Phenotype; Population; Population Control; Property; Public Health; Structure of germinal center of lymph node; T-Lymphocyte; Tissues; Translating; Vaccinated; Vaccination; Vaccines; base; exhaust; flu; influenza virus vaccine; innovation; lymph nodes; mortality; mouse model; peripheral blood; programs; response; senescence; transcriptome; vaccine response

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.

描述（申请人提供）：根据 CDC 的数据，每年有超过 20,000 人因流感死亡和 200,000 人住院，其中 90% 为 65 岁以上人群。季节性三价灭活流感疫苗的接种仍然是公众的主要接种方式疾病预防控制中心建议的健康措施；然而，对于最需要保护的老年人群来说，这种疫苗的功效显着降低，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，老年人疫苗失败的潜在机制（对流感疫苗免疫无反应）仍有待确定。疫苗接种的大多数关键免疫反应发生在区域引流淋巴结 (LN) 内，而不是外周血中。有鉴于此，该提案的核心新颖性和创新之处在于定义区域引流淋巴结内潜在的 B 和 T 细胞特性，这些特性可以解释老年人的免疫无反应和疫苗接种失败。在这里，我们建议直接检查疫苗接种后获得的近端淋巴结活检中流感疫苗诱导的 CD4+ T 和 B 细胞。 最近对小鼠的研究发现，滤泡辅助 T (Tfh) 细胞在接种疫苗后 LN 生发中心的发育中发挥关键作用，为 B 淋巴细胞提供最佳刺激，从而通过高亲和力抗体形成持久的体液免疫。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，对于对流感疫苗没有反应的老年人群体来说更是如此。因此，我们假设滤泡辅助性 T 细胞 (Tfh) 和 1 型辅助性 T (Th1) 转录编程、水平、表型和功能的缺陷导致老年人接种流感疫苗后抗体数量和质量降低，临床上转化为非- 反应能力和疫苗失败。此外，我们假设这些缺陷在老年疫苗无反应者中最为明显，并导致在老年人中观察到的免疫衰老表型。我们将在以下具体目标中解决这些假设： 目标 1：确定接种疫苗前 LN 和血液中总和流感特异性 CD4+ Th1/Tfh 亚群和 B 细胞的基线差异是否可以预测旧流感疫苗失败/无反应者（ NR）和老疫苗反应者（R）。目标 2：确定流感疫苗接种后局部 LN 和血液中 CD4+ Th1/Tfh 细胞和 B 细胞反应急性诱导的具体缺陷，从而导致旧流感疫苗 NR 和 R 表型。