Dysfuntional antigen presenting cell responses to influenza in geriatric individu

描述(申请人提供)：随着基因工程的最新进展，人们担心大流行性流感或禽流感可能会成为一种生物恐怖因子。此外，大多数(90%)死于流感的人年龄在65岁或以上。老年人对目前的流感疫苗制剂的反应不佳，保护性抗体滴度显著降低。虽然与年龄相关的T细胞功能下降已被证实，并正在积极研究，但关于衰老如何影响抗原提呈细胞(APC)，人们知之甚少。这些细胞(特别是树突状细胞(DC))对于诱导体液免疫和细胞免疫都是至关重要的。我们的初步数据表明，在老年个体中，DC产生的干扰素-α异常升高，而IL-12的产生受到抑制。这种细胞因子模式可能会导致辅助性T细胞生成的下降。此外，我们的数据表明，老年人DC中II类MHC(MHC-II)水平降低。这可能会导致DC的抗原提呈减少，从而导致CD4+T辅助细胞的生成不佳。 我们的总体假设是，APC缺陷导致老年患者T和B细胞对流感的反应降低。更好地了解老年性APC的具体缺陷可能会使有针对性的方法为老年人设计疫苗。我们将以以下具体目标来处理这一问题： 目的1.研究老年人树突状细胞(DC)对流感先天免疫应答的特异性缺陷。我们将比较65岁和21-35岁人群中浆细胞样树突状细胞和髓系树突状细胞对流感的先天反应。具体地说，我们将分析DC在流感刺激后产生细胞因子和趋化因子，以及成熟、共刺激和归巢标记。我们将研究老年性DC细胞因子失调的几种可能机制。 目的2.确定老年人DC和B细胞在抗原加工和流感表现过程中是否存在MHC II类缺陷。我们将使用人类白细胞抗原-DR匹配的T细胞杂交瘤来确定老年人DC和B细胞中MHC-II抗原对流感的处理和呈递是否存在缺陷。如果观察到缺陷，将探索缺陷的机理。B细胞的AG处理和提呈效率对于它们接受来自CD4+T辅助细胞的最佳共刺激是重要的。

DESCRIPTION (provided by applicant): With recent advances in genetic engineering there is concern that pandemic influenza or avian influenza might emerge as a bioterror agent. In addition, the majority of deaths (90%) attributed to influenza are in persons age 65 or older. Elderly individuals have suboptimal responses to current influenza vaccine preparations and significantly reduced levels of protective antibody titers. While age-related decline in T cell function has been demonstrated and is being actively investigated, remarkably little is known about how aging affects Ag presenting cells (APC). These cells (especially dendritic cells (DC)) are critical for induction of both humoral and cell mediated immunity. Our preliminary data suggests abnormally elevated IFN-a and depressed IL-12 production by DC in geriatric individuals. This cytokine pattern may lead to a decline in T helper cell generation. In addition our data suggests that class II MHC (MHC-II) levels are reduced in DC in geriatric individuals. This could result in reduced Ag presentation by DC leading to suboptimal generation of CD4+ T helper cells. It is our overall hypothesis that APC defects contribute to decreased T and B cell responses to influenza in geriatrics. A better understanding of specific defects in geriatric APC might allow a targeted approach to engineer vaccines for the elderly. We will approach this with the following specific aims: Aim 1. To determine the specific defects in innate immune responses of DC to influenza in geriatric individuals. We will compare innate responses of plasmacytoid DC and myeloid DC to influenza in individuals aged >65 and those aged 21-35. Specifically, we will analyze DC for production of cytokines and chemokines, and maturation, costimulation, and homing markers after influenza stimulation. We will examine several potential mechanisms for the cytokine dysregulation in geriatric DC. Aim 2. To determine if DC and B cells from geriatric individuals have a MHC class II defect in Ag processing and presentation of influenza. We will determine if MHC-II Ag processing and presentation of influenza in DC and B cells from elderly individuals is defective using HLA-DR matched T cell hybridomas. If defects are observed, mechanisms of the defects will be explored. Ag processing and presentation efficiency of B cells is important for them to receive optimal costimulation from CD4+ T helper cells.