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

浆细胞样树突状细胞、IFN-α、Th-1 反应

• 批准号: 6757906
• 负责人: Frederick Paul Siegal
• 金额: $ 20.61万
• 依托单位: SAINT VINCENT CATHOLIC MED CTRS OF NY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757906
• 关键词: AIDS; AIDS therapy; HIV infections; antiAIDS agent; clinical research; corticosteroids; delayed hypersensitivity; dendritic cells; helper T lymphocyte; hepatitis A; hepatitis vaccine; hormone therapy; human immunodeficiency virus; human subject; humoral immunity; immunodeficiency; interferon alpha; interferon gamma; leukocyte activation /transformation; microorganism immunology; patient oriented research; protein biosynthesis

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.

描述（由申请人提供）：拟议的研究将解决这样的假设：最近发现的一种细胞类型，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，pDC已被证明是血液和组织中干扰素(IFN)- α的主要产生者，并作为先天免疫系统的一部分发挥作用。人们认为，pDCs在周围遇到微生物抗原并迁移到次级淋巴器官，在那里它们也通过局部产生ifn - α和其他细胞因子影响微环境中的幼稚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ifn - γ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，将对循环pDC数量正常、减少或无法检测到的人类受试者接种一种他们之前没有接种过的疫苗。甲型肝炎疫苗是一种经fda批准的免疫原，耐受性良好，通常用于人类临床适应症，将是首选疫苗。该研究的主要终点将是受试者的CD4+ T细胞在接受免疫一个月后体外产生ifn - γ的能力，与基线结果相比。监测免疫期间CD4+ T细胞数量、幼稚CD4+CD45RA+CD62L+ T细胞数量、pDC数量和功能、免疫原的迟发型超敏反应和血清学反应以及临床数据。研究对象包括：不同年龄的健康志愿者；接受积极抗逆转录病毒疗法治疗严重免疫缺陷的艾滋病毒感染者；已成功停止抗病毒治疗的艾滋病毒感染者；常见、可变免疫缺陷患者；以及接受皮质类固醇疗程的病人或健康志愿者。在所有这些情况下，有一个pDC可用谱，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，会出现pDC数量，ifn - α生成的严重缺陷，或两者都存在。通过使用多元统计分析，将定义功能性、产生ifn的pDC对Th-1免疫反应的影响。