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岁人群感染性住院和死亡的最常见原因， 年龄越大，流感疫苗的有效性就越低。有效的免疫反应需要 免疫系统的先天和适应性武器之间的适当相互作用以及适当的平衡 的激活和调节。衰老影响免疫系统的多个组成部分，我们建议， 在接种疫苗之前存在的老化免疫系统的累积缺陷和不平衡有助于 疫苗效果。该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细胞数量较低或功能障碍是否 接种疫苗前的幼稚T细胞与宿主T和B细胞对季节性免疫应答的发展有关。 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， 通过ELISPOT（IFNγ）测定这些参数是否与宿主流感特异性T细胞应答相关 和IL 2）和通过ELISA和血凝抑制测定（HAI）的抗体应答。我们会特别 注意一种新的T细胞亚群，它们在具有幼稚表型的老年记忆T细胞（Tmnp）中扩增。 这些细胞表达淋巴结归巢受体CCR 7，但在转录和功能上不同于 幼稚细胞在目的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 与来自流感、CMV和EBV的常见病毒抗原进行比较。在目标2中，我们将检查 老年人中既存单核细胞/巨噬细胞表型对流感疫苗应答的贡献。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和B细胞对流感疫苗的应答相关。 我们将通过测量血浆炎症和抗炎症因子水平来检查全身环境。 炎性细胞因子目的2a探讨老年人全身微环境对单核细胞的影响。 巨噬细胞分化。我们将在以下条件下产生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调节性（Treg）或 免疫前功能失调的调节性T细胞（TregDys）频率与免疫应答受损有关。 老年人接种流感疫苗虽然先前的研究表明，血浆TGFβ水平升高， 以及随着年龄的增长而累积，这与炎症的公认观察结果相矛盾。在Aim 3a中 我们将检验另一种假设，即M2单核细胞驱动TcB的发展，但由于M2单核细胞的高表达， 在老年人中IL-6的水平，这些T细胞是功能失调的（TregDys）。我们认为IL-6水平的升高驱动了 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阻断的体外试验来研究IL-6在 促进TregDys细胞。这项提议的结果将提供对免疫表型的深入了解， 在老年人接种流感疫苗之前，它预示着疫苗应答较差。免疫参数 老年人和年轻人在接种疫苗前的死亡率将使我们能够对目前的疫苗接种实践提出改进建议。 在老年人中。

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.