Th1 and Th2 Responses in Viral Immunity

描述（由申请人提供）：根据我们自己的结果和其他人产生的数据，我们得出结论，树突状细胞（dc）是决定病毒感染产生的免疫反应性质的关键因素。特别是，我们的数据表明，流感或仙台病毒感染的dc经历了与共刺激分子和MHC表达增加以及导致Th1免疫应答的关键细胞因子释放相关的成熟事件。我们假设dc中的这些成熟变化与病毒复制密切相关，病毒复制与触发分子（如dsRNA）的产生和干扰素途径的激活有关。不幸的是，关于病毒对DC成熟的直接影响的数据很少，与体内收集的细胞相关的证据更少。因此，我们建议研究根据toll样受体（TLRs）启动DC成熟的结果选择的适配蛋白和转录因子的作用。此外，我们的数据表明介导体如IRF3参与干扰素的诱导。我们提出两种方法来阐明关键因素。在第一项研究中，我们将利用小鼠，其中涉及产生被怀疑起关键作用的元件的基因已被删除。因此，我们将使用IRF-3、MyD88、1型干扰素受体和STAT1基因被删除的小鼠。我们的第二种方法将使用仙台Cantell病毒的反向遗传系统来创建重组病毒，其中引入了与DC成熟或干扰素诱导抑制相关的基因。这些基因将包括已知具有抗干扰素活性的病毒的遗传成分。它们还将包括干扰素途径或TLR途径中重要遗传元件的显性阴性突变体。该系统的价值在于仙台病毒是小鼠的天然病原体，我们将使用的特定菌株是我们在诱导DC成熟方面测试过的最有效的病毒。此外，我们建议进一步研究RSV，在初步观察中，RSV产生一种不寻常的DC成熟模式，并导致具有不寻常特征的免疫反应。因此，仅研究了有限的病毒，我们意识到不同的病毒对DC成熟表现出不同的影响，并导致不同类型的免疫反应。

DESCRIPTION (provided by applicant): On the basis of our own results and data generated by others, we have concluded that dendritic cells (DCs) are a key element involved in dictating the nature of the immune response generated by virus infection. In particular, our data demonstrate that influenza or Sendai virus infected DCs undergo maturational events associated with increased expression of costimulatory molecules and MHC and release of key cytokines leading to Th1 immune responses. We hypothesize that these maturational changes in DCs are closely linked to virus replication associated with the production of triggering molecules such as dsRNA and activation of the interferon pathway. Unfortunately, there is little data on the direct effect of virus on maturation of DC and even less evidence related to in vivo collected cells. Thus, we propose to investigate the roles of adapter proteins and transcription factors chosen based on results of DC maturation initiated through toll like receptors (TLRs). Additionally, our data suggest involvement of mediator such as IRF3 known to be involved in the induction of interferon. We propose two approaches to elucidate the key factors. In the first, we will utilize mice in which genes involved in producing elements that are suspected of playing a key role have been deleted. Thus, we will employ mice in which genes for IRF-3, MyD88, type 1 interferon receptor and STAT1 have been deleted. Our second approach will use a reverse genetics system with Sendai Cantell virus to create recombinant viruses in which genes associated with DC maturation or inhibition of interferon induction have been introduced. These genes will include genetics elements of viruses known to have anti-interferon activity. They will also include dominant negative mutants of important genetic elements in the interferon pathway or TLR pathways. The value of this system is that Sendai virus is a natural pathogen of mice and the particular strain that we will employ is the most potent virus we have tested in the induction of DC maturation. In addition we propose to further investigate RSV, which in preliminary observations produces an unusual pattern of DC maturation and results in an immune response with unusual characteristics. Thus, having examined only a limited array of viruses, we are aware that different viruses exhibit different effects on DC maturation and result in different types of immune responses.