Plasmacytoid dendritic cells, IFN-alpha, Th-1 response

描述（由申请方提供）：拟定的研究将阐明以下假设：最近认识到的细胞类型，浆细胞样树突状细胞（pDC），是人体细胞介导（Th-1）免疫应答产生的重要参与者，pDC已被证明是血液和组织中干扰素（IFN）-α的主要生产者，并作为先天免疫系统的一部分发挥作用。据信pDC在外周遇到微生物抗原并迁移到次级淋巴器官，在那里它们还通过局部产生IFN-α和其他细胞因子影响该微环境中的幼稚T细胞和其他单核细胞。这导致克隆选择的适应性免疫应答，其特征在于产生IFN-γ和表征Th-1应答的其它细胞因子。为了检验该假设，具有正常、减少或不可检测数量的循环pDC的人类受试者将用他们先前没有经验的疫苗免疫。甲型肝炎疫苗是一种FDA批准的免疫原，耐受性良好，通常在临床上适用于人类，将是首选的疫苗。本研究的主要终点将是受试者的CD 4 + T细胞在接受免疫接种后一个月体外产生IFN-γ的能力，与基线结果相比。将监测CD 4 + T细胞数量、初始CD 4 + CD 45 RA + CD 62 L + T细胞数量、免疫期间pDC数量和功能、对免疫原的迟发型超敏反应和血清学反应以及临床数据。研究受试者将包括：年龄范围内的健康志愿者;正在用活性抗逆转录病毒疗法治疗严重免疫缺陷的HIV感染患者;正在停止成功的抗病毒疗法的HIV感染患者;普通、可变免疫缺陷患者;以及正在接受皮质类固醇疗程的患者或健康志愿者。在所有这些情况下，存在pDC可用性谱，而T细胞数量可能受影响较小。我们的经验表明，在这些类别中的一些人中，pDC数量、IFN-α生成或两者的严重缺陷将存在。通过使用多变量统计分析，将确定功能性产生IFN的pDC对Th-1免疫应答的影响。

DESCRIPTION (provided by applicant): The proposed studies will address the hypothesis that a recently recognized cell type, the plasmacytoid dendritic cell (pDC), is an important participant in the production of cell-mediated (Th-1) immune responses in humans, pDC have been shown to be the principal producers of interferon (IFN)-alpha in the blood and tissues, and function as part of the innate immune system. It is believed that pDCs encounter microbial antigens in the periphery and migrate to secondary lymphoid organs, where they also influence naive T cells and other mononuclear cells in this microenvironment through the local production of IFN-alpha and other cytokines. This leads to a clonally selected, adaptive immune response characterized by the production of IFN-gamma and other cytokines that characterize the Th-1 response. To test the hypothesis, human subjects with either normal, reduced or undetectable numbers of circulating pDC will be immunized with a vaccine with which they have had no prior experience. Hepatitis A vaccine, an FDA-approved immunogen that is well tolerated and often clinically indicated in humans will be the vaccine of choice. The principal endpoint of the study will be the ability of the subjects' CD4+ T cells to generate IFN-gamma in vitro a month after receiving the immunization, compared to results at baseline. Numbers of CD4+ T cells, naive CD4+CD45RA+CD62L+ T cells, pDC number and function during the period of immunization, delayed-type hypersensitivity and serologic response to the immunogen, and clinical data will be monitored. Study subjects will include: healthy volunteers over a range of ages; patients with HIV infection being treated for severe immunodeficiency with active antiretroviral therapy; patients with HIV infection whose successful antiviral therapy is being stopped; patients with common, variable immunodeficiency; and patients or healthy volunteers undergoing courses of corticosteroids. In all these situations, there is a spectrum of pDC availability, while T cell numbers may be less affected. Our experience indicates that in some people in these categories, profound deficits of pDC number, IFN-alpha generation, or both will be present. Through the use of multivariate statistical analysis, the influence of functional, IFN-producing pDC on Th-1 immune responses will be defined.