MECHANISMS OF IMMUNOPATHOLOGY IN DHF/DSS

本计划项目的目标是了解免疫病理学的 登革出血热（DHF）和登革休克综合征（DSS）， 登革热病毒感染的并发症。 DHF/DSS的频率多 在二次感染登革热病毒株时， 与引起初次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 的发病率和死亡率 严重的登革热感染是一个主要的公共卫生问题， 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 从单纯性登革热（D）进展为DDS/DSS， 在疾病过程的早期确定： 外周血单个核细胞，细胞因子的水平产生作为一个 登革热感染单核细胞和T淋巴细胞活化的结果， 单核细胞 项目#2将建立登革热特异性的分子理解 严重登革热感染时人T淋巴细胞和单核细胞反应。 登革特异性人CD 4 + T辅助细胞1和2亚群将在 克隆水平 将定义DHF/DSS和D中的TcR使用。 细胞因子 从急性登革热感染期间获得的单核细胞的生产将是 测定 病毒和感染性病毒抗体的血浆滴度 复合体将被确定。 我们将了解是否存在相关性 这些参数和疾病活动之间的关系。 项目#3将确定儿童登革热病毒分离株的序列 与DHF/DSS或D确定是否有一致的序列 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 细胞对免疫病理学的理解DHF/DSS作为 对高危儿童的早期诊断，作为制定 合理和安全的干预措施和疫苗方法来预防这种情况 严重的疾病。

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.