MECHANISMS OF IMMUNOPATHOLOGY IN DHF/DSS

DHF/DSS 的免疫病理学机制

• 批准号: 2003971
• 负责人: FRANCIS ANTHONY ENNIS
• 金额: $ 96.82万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1998-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2003971
• 关键词: dengue; dengue virus; immunopathology

The goal of this Program Project is to understand the immunopathology of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the severe complications of dengue virus infections. The frequency of DHF/DSS is much greater during secondary infections with dengue virus strains of a different dengue serotype than that which caused the primary infection. These immunopathological results have slowed down vaccine development because of safety concerns. The morbidity and mortality associated with severe dengue infections is a major public health problem which is increasing in frequency. We propose to define the molecular and cellular basis of the immunopathology associated with severe dengue infections. Project #1 consists of clinical investigations in Thailand. Quantitative markers of dengue infection and immune responses that may correlate with progression from uncomplicated dengue fever (D) to DDS/DSS will be determined early in the disease process: the number of dengue-infected peripheral blood mononuclear cells, the levels of cytokines produced as a result of dengue infection of monocytes and activation of T lymphocytes and monocytes. Project #2 will establish a molecular understanding of dengue specific human T lymphocyte and monocyte responses during severe dengue infections. Dengue specific human CD4+ T helper 1 and 2 subsets will be defined at the clonal level. TcR usage in DHF/DSS and D will be defined. Cytokine production from monocytes obtained during acute dengue infections will be determined. Titers in plasma of virus and infectious virus-antibody complexes will be determined. We will learn whether correlations exist between these parameters and disease activity. Project #3 will define the sequence of dengue virus isolates from children with DHF/DSS or D to determine whether there are consistent sequence differences. A Clinical Research Core and a Molecular Immunology Core are needed to support these research projects. An Administrative Core will be responsible for directing, coordinating and overseeing this Program Project. Our ultimate goal is to develop an improved molecular and cellular understanding of the immunopathology DHF/DSS as a basis for the earlier diagnosis of children at highest risk, as a basis for developing logical and safe interventions and vaccine approaches to prevent this severe illness.

该计划项目的目标是了解免疫病理学 登革热出血热 (DHF) 和登革热休克综合征 (DSS) 登革热病毒感染的并发症。 DHF/DSS 的频率很多 在登革热病毒株继发感染期间更大 与引起原发感染的登革热血清型不同。 这些免疫病理学结果减缓了疫苗的开发 出于安全考虑。 发病率和死亡率与 严重的登革热感染是一个重大的公共卫生问题 频率增加。 我们建议定义分子和细胞 与严重登革热感染相关的免疫病理学基础。 项目#1 包括在泰国进行的临床研究。 定量 登革热感染和免疫反应的标志物可能与 从简单的登革热 (D) 到 DDS/DSS 的进展将是 在疾病过程的早期确定：感染登革热的人数 外周血单核细胞，产生的细胞因子水平 单核细胞登革热感染和T淋巴细胞活化的结果 单核细胞。 项目 #2 将建立对登革热特异性的分子理解 严重登革热感染期间人类 T 淋巴细胞和单核细胞的反应。 登革热特异性人类 CD4+ T 辅助细胞 1 和 2 子集将在 克隆水平。 将定义 DHF/DSS 和 D 中的 TcR 使用。 细胞因子 急性登革热感染期间获得的单核细胞的产量将是 决定。 病毒血浆滴度和传染性病毒抗体 复合物将被确定。 我们将了解是否存在相关性 这些参数与疾病活动之间的关系。 项目 #3 将定义从儿童身上分离出的登革热病毒序列 用DHF/DSS或D判断序列是否一致 差异。 需要临床研究核心和分子免疫学核心 支持这些研究项目。 行政核心将是 负责指导、协调和监督本计划 项目。 我们的最终目标是开发一种改进的分子和 免疫病理学 DHF/DSS 的细胞理解作为基础 对高危儿童进行早期诊断，作为发展的基础 合理且安全的干预措施和疫苗方法可以预防这种情况 重病。