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

描述(申请人提供)：拟议的研究将解决一种新发现的细胞类型，浆细胞样树突状细胞(PDC)是人类细胞介导(Th-1)免疫反应产生的重要参与者的假设，PDC已被证明是血液和组织中干扰素(干扰素)-α的主要产生者，并作为天然免疫系统的一部分发挥作用。据认为，pDC在周围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干扰素-α和其他细胞因子影响这个微环境中的初始T细胞和其他单核细胞。这导致了一种克隆选择的适应性免疫反应，其特征是产生干扰素-伽马和其他细胞因子，这些细胞因子是Th-1反应的特征。为了验证这一假设，循环PDC数量正常、减少或检测不到的人类受试者将被接种一种他们以前没有接种过的疫苗。甲型肝炎疫苗是FDA批准的一种免疫原，耐受性良好，经常在临床上用于人类，将是首选疫苗。这项研究的主要终点将是受试者接受免疫一个月后，与基线结果相比，受试者的CD4+T细胞在体外产生干扰素-伽马的能力。将监测免疫期间的CD4+T细胞数量、初始CD4+CD45RA+CD62L+T细胞、PDC数量和功能、迟发型超敏反应和对免疫原的血清学反应，以及临床数据。研究对象将包括：不同年龄的健康志愿者；正在接受积极抗逆转录病毒治疗的严重免疫缺陷患者；成功停止抗病毒治疗的艾滋病毒感染患者；常见的可变免疫缺陷患者；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，PDC的可用性是不同的，而T细胞数量可能受到的影响较小。我们的经验表明，在这些类别的一些人中，会出现严重的PDC数量和/或干扰素-α生成缺陷。通过使用多元统计分析，将确定功能性的、产生干扰素的PDC对Th-1免疫反应的影响。

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.