Impact of preexisting immune profile in elderly on influenza vaccine response

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岁以上人群中感染性住院和死亡的最常见原因 然而，流感疫苗的效力随着年龄的增长而降低。有效的免疫反应需要 免疫系统的先天和适应性手臂之间的适当相互作用和适当的平衡 激活和调节。衰老影响免疫系统的多个组成部分，我们认为 在接种疫苗前存在的老化免疫系统中的累积缺陷和失衡有助于 疫苗结果。这个应用程序将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 季节性流感疫苗。目标1将确定年龄较大、幼稚T细胞数量较少或功能障碍 接种前的幼稚T细胞与宿主T和B细胞对季节性免疫反应的发展有关 流感疫苗。我们将在接种前评估PBMC样本中的年龄和幼稚T细胞表型 确定这些参数是否与ELISPOT(干扰素γ)的宿主流感特异性T细胞反应相关 和IL2)，抗体反应采用酶联免疫吸附试验和血凝抑制试验。我们会付特价的 注意一种新的T细胞亚群，它在具有幼稚表型(Tmnp)的老年记忆T细胞中扩增。 这些细胞表达淋巴归巢受体CCR7，但在转录和功能上与 幼稚的细胞。在目标1a中，我们将通过检测老年人Tmnp细胞的特异性来确定其抗原特异性。 使用四聚体对流感、巨细胞病毒和EB病毒的常见病毒抗原。在目标2中，我们将研究 老年人预先存在的单核/巨噬细胞表型对流感疫苗应答的贡献。我们会 直接体外流式细胞仪检测老年患者外周血单核细胞表型 确定接种前的表型是否与T和B细胞对流感疫苗的反应有关。 我们将通过测量血浆炎症和抗炎因子的水平来检查全身环境 炎性细胞因子。目的2a检测老年全身微环境对单核细胞的影响。 衍生的巨噬细胞分化。我们将在存在的情况下产生单核细胞衍生巨噬细胞(MDM) 然后分析炎症(M1)或交替激活(M2)的发展情况 巨噬细胞和比较老年和年轻的MDM。在目标3中，我们将确定T调节(Treg)或 T调节功能障碍(TregDys)细胞频率预接种与免疫反应受损有关 在老年人中接种流感疫苗。尽管先前的研究表明，血浆中转化生长因子β水平升高 随着年龄的增长，Tregs的积累，这与炎症的公认观察结果相矛盾。在目标3a中 我们将检验另一种假设，即M2单核细胞推动Tregs的发育，但由于 IL-6水平在老年人中，这些树是功能失调的(TregDys)。我们认为，IL-6水平的升高会推动 TregDys的发展，这有助于老年人持续的慢性炎症。为此，我们 将使用自体血清和IL-6阻断的体外实验来研究IL-6在血管内皮细胞瘤中的作用机制。 促进TregDys细胞。这一建议的结果将提供对免疫表型的洞察 在老年人接种流感疫苗之前，预测疫苗反应较差。免疫学参数 老年人和年轻人之前接种疫苗将使我们能够对目前的疫苗接种做法提出改进建议 在老年人身上。

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.