Impact of preexisting immune profile in elderly on influenza vaccine response

老年人原有免疫特征对流感疫苗反应的影响

• 批准号: 10485431
• 负责人: Carey Lynn Shive
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485431
• 关键词: Adjuvant; Affect; Age; Age Years; Aging; Anti-Inflammatory Agents; Antibody Response; Antigens; Attention; Autologous; B-Lymphocytes; Biological Assay; Biological Response Modifiers; Blocking Antibodies; CD4 Positive T Lymphocytes; Cell Count; Cell physiology; Cells; Cessation of life; Chronic; Clinic; Complex; Cytomegalovirus; Defect; Development; Effectiveness; Elderly; Environment; Enzyme-Linked Immunosorbent Assay; Equilibrium; FOXP3 gene; Flow Cytometry; Frequencies; Future; Genetic Transcription; Health; Hemagglutination; Hemagglutinin; Hospitalization; Human Herpesvirus 4; IL2 gene; IL2RA gene; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunization; Immunologic Memory; Immunologics; Impairment; Inflammation; Inflammatory; Influenza; Influenza vaccination; Innate Immune System; Interferon Type II; Interleukin-6; Invaded; Lymphocyte Homing Receptors; Lymphopenia; Macrophage; Malignant Neoplasms; Measures; Medical center; Morbidity - disease rate; Outcome; Participant; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Plasma; Pneumonia; Population; Recovery; Regulation; Regulatory T-Lymphocyte; Role; Sampling; Serum; Specificity; Suggestion; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transforming Growth Factor beta; Vaccination; Vaccines; Veterans; Viral Antigens; adaptive immune response; antigen-specific T cells; arm; cytokine; emerging pathogen; enzyme linked immunospot assay; human old age (65+); improved; in vitro Assay; influenza virus vaccine; insight; monocyte; novel; older patient; participant enrollment; pathogen; response; seasonal influenza; vaccination outcome; vaccine response; young adult

The decline in immunity with age results in poor responses to vaccines and novel pathogens. Pneumonia and influenza are the most common causes of infectious hospitalization and death in people who are > 65 years of age and yet the effectiveness of influenza vaccine lessens with age. An effective immune response requires the appropriate interaction between the innate and the adaptive arms of the immune system and the proper balance of activation and regulation. Aging affects multiple components of the immune system and we propose that the cumulative defects and imbalances in the aging immune system that exist before vaccination contribute to vaccine outcomes. This application will examine immune phenotypes in elderly and young participants before annual influenza vaccination and determine how these phenotypes affect the B cell and T cell responses to seasonal influenza vaccine. Aim 1 will determine whether older age, lower naïve T cell number or dysfunctional naïve T cells prior to vaccination is associated with development of host T and B cell response to seasonal influenza vaccine. We will evaluate age and naïve T cell phenotype in PBMC samples before vaccination to determine whether these parameters correlate with host influenza specific T cell responses by ELISPOT (IFNγ and IL2) and antibody responses by ELISA and hemagglutination inhibition assay (HAI). We will pay special attention to a novel subset of T cells that are expanded in elderly, memory T cells with a naïve phenotype (Tmnp). These cells express the lymph node homing receptor CCR7 but are transcriptionally and functional distinct from naïve cells. In Aim 1a we will determine the antigen specificity of Tmnp cells in elderly by examining their specificity to common viral antigens from influenza, CMV, and EBV using tetramers. In Aim 2, we will examine the contribution of preexisting monocyte/macrophage phenotypes in elderly to influenza vaccine responses. We will examine the phenotype of peripheral monocytes in elderly patients directly ex vivo using flow cytometry and determine if the phenotype before vaccination is associated with the T and B cell response to influenza vaccine. We will examine the systemic environment by measuring plasma levels of both inflammatory and anti- inflammatory cytokines. Aim 2a will examine the influence of the elderly systemic microenvironment on monocyte derived macrophage differentiation. We will generate monocyte-derived macrophages (MDM) in the presence of autologous serum and then analyze the development of inflammatory (M1) or alternatively activated (M2) macrophages and compare elderly and young MDM. In Aim 3 we will determine if T regulatory (Treg) or dysfunctional T regulatory (TregDys) cell frequencies prevaccination are associated with impaired response to influenza vaccine in the elderly. Although previous studies suggest there are elevated plasma levels of TGFβ and an accumulation of Tregs with age, this contradicts the well-established observation of inflamaging. In Aim 3a we will test an alternative hypothesis that M2 monocytes drive the development of Tregs, but because of the high levels of IL-6 in elderly, these Tregs are dysfunctional (TregDys). We propose that elevated levels of IL-6 drive the development of TregDys and that this contributes to persistent chronic inflammation in the elderly. To this end, we will use in vitro assays with autologous serum and IL-6 blockade to investigate the mechanistic role of IL-6 in promoting TregDys cells. Results from this proposal will provide insight into the immunologic phenotype that precedes influenza vaccination in elderly and is predictive of poor vaccine response. Immunologic parameters of elderly and young preceding vaccination will permit us to propose improvements to current vaccine practices in the elderly.

随着年龄的增长，免疫力下降，导致对疫苗和新病原体的反应不佳。肺炎和 流感是 65 岁以上人群感染性住院和死亡的最常见原因 年龄，但流感疫苗的有效性会随着年龄的增长而减弱。有效的免疫反应需要 免疫系统的先天性和适应性臂之间适当的相互作用以及适当的平衡 的激活和调节。衰老会影响免疫系统的多个组成部分，我们建议 疫苗接种前存在的老化免疫系统的累积缺陷和不平衡会导致 疫苗结果。该应用程序将在测试之前检查老年人和年轻参与者的免疫表型 每年接种流感疫苗并确定这些表型如何影响 B 细胞和 T 细胞对流感的反应 季节性流感疫苗。目标 1 将确定是否年龄较大、初始 T 细胞数量较低或功能失调 疫苗接种前的幼稚 T 细胞与宿主 T 和 B 细胞对季节性反应的发展有关 流感疫苗。在接种疫苗之前，我们将评估 PBMC 样本中的年龄和幼稚 T 细胞表型 通过 ELISPOT (IFNγ 和 IL2) 以及通过 ELISA 和血凝抑制测定 (HAI) 进行的抗体反应。我们将特别支付 关注一种新的 T 细胞亚群，该亚群在具有幼稚表型 (Tmnp) 的老年记忆 T 细胞中扩增。 这些细胞表达淋巴结归巢受体 CCR7，但在转录和功能上与 幼稚细胞。在目标 1a 中，我们将通过检查老年人 Tmnp 细胞的特异性来确定其抗原特异性 使用四聚体识别来自流感、CMV 和 EBV 的常见病毒抗原。在目标 2 中，我们将检查 老年人中先前存在的单核细胞/巨噬细胞表型对流感疫苗反应的贡献。我们将 使用流式细胞术直接离体检查老年患者的外周单核细胞表型， 确定疫苗接种前的表型是否与 T 细胞和 B 细胞对流感疫苗的反应相关。 我们将通过测量炎症和抗氧化剂的血浆水平来检查全身环境。 炎症细胞因子。目标2a将考察老年人全身微环境对单核细胞的影响 衍生巨噬细胞分化。我们将在存在以下物质的情况下生成单核细胞衍生的巨噬细胞（MDM）： 自体血清，然后分析炎症 (M1) 或替代激活 (M2) 的发展 巨噬细胞并比较老年人和年轻的 MDM。在目标 3 中，我们将确定 T 调节 (Treg) 或 免疫前功能失调的 T 调节 (TregDys) 细胞频率与免疫反应受损有关 老年人接种流感疫苗。尽管之前的研究表明血浆 TGFβ 水平升高 而且 Tregs 会随着年龄的增长而积累，这与公认的炎症观察相矛盾。目标 3a 我们将测试另一种假设，即 M2 单核细胞驱动 Tregs 的发育，但由于高 老年人的 IL-6 水平较低，这些 Treg 功能失调 (TregDys)。我们认为 IL-6 水平升高会驱动 TregDys 的发展，这会导致老年人持续的慢性炎症。为此，我们 将使用自体血清和 IL-6 阻断的体外测定来研究 IL-6 在 促进 TregDys 细胞。该提案的结果将提供对免疫表型的深入了解 先于老年人接种流感疫苗，并预示疫苗反应不佳。免疫学参数 老年人和年轻人之前接种疫苗的情况将使我们能够对当前的疫苗接种实践提出改进建议 在老年人中。