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: 6589799
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6589799
• 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）：拟议的研究将解决以下假设：最近公认的细胞类型浆细胞类树突状细胞（PDC）是人类中细胞介导的（TH-1）免疫反应的重要参与者PDC，PDC已被证明是Interferon（IFN）-Alpha的主要生产者（IFN） - Altrate-Altrate Insrate和System and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and and Fighte and Fincor。据认为，PDCS在周围会遇到微生物抗原并迁移到次级淋巴机构，在那里它们还通过本地生产IFN-Alpha和其他细胞因子来影响这种微环境中天真的T细胞和其他单核细胞。这导致了一种克隆选择的自适应免疫反应，其特征是产生IFN-gamma和其他表征Th-1反应的细胞因子。为了检验该假设，具有正常，减少或无法检测到的循环PDC数量的人类受试者将通过没有先前经验的疫苗进行免疫。肝炎A疫苗，一种经FDA批准的免疫原，可耐受性且经常在人类中临床表明的免疫原是选择的疫苗。与基线相比，研究的主要终点是受试者的CD4+ T细胞在接受免疫后一个月在体外生成IFN-gamma的能力。 CD4+ T细胞的数量，幼稚的CD4+ CD45RA+ CD62L+ T细胞，PDC的数量和功能，在免疫期，延迟型超敏反应和对免疫原的血清学反应，并将监测临床数据。研究对象将包括：多个年龄段的健康志愿者；患有HIV感染的患者通过主动抗逆转录病毒治疗治疗严重的免疫缺陷；成功的抗病毒疗法的艾滋病毒感染患者正在停止；具有常见，可变免疫缺陷的患者；以及正在接受皮质类固醇课程的患者或健康的志愿者。在所有这些情况下，都有PDC的可用性范围，而T细胞数量可能较少。我们的经验表明，在这些类别中的某些人中，PDC数字，IFN-Alpha产生或两者都会存在。通过使用多元统计分析，将定义功能，IFN产生PDC对Th-1免疫反应的影响。