Dendritic cell function in schistosomiasis

描述：（由申请人提供）：这是一份修订后的新申请， 研究树突状细胞（DC）在诱导Th 2应答中的作用， 嗜酸性抗原。启动对细胞外 当DC将抗原（Ag）肽呈递给 CD 4+辅助性T（Th）细胞。这个信号，沿着重要的共刺激信号 从其他DC表面分子，促进T细胞的克隆扩增 表达相关TCR。此后，免疫反应集中，使得 大多数Th细胞继续产生类似的效应细胞因子组。 结果通常是由Th 1或Th 2细胞主导的免疫应答，其中 Th 1细胞产生IFN-γ和IL-2，而Th 2细胞产生IL-4、IL-5、IL-6、IL-10和IL-10。 -13.转录因子T-bet或GATA 3的表达分别为 对于获得Th 1或Th 2表型是必需的。IL-12强烈选择 IL-4选择Th 2细胞。DC参与Th 1， IL-12直接响应某些微生物病原体和在连接 CD 40通过CD 154。然而，很少有人知道DC对病原体的反应， 诱导Th 2应答。要检验的假设是，通过认识到 病原体相关的分子模式，对抗原的反应方式， 还没有被充分描述，但这与他们对 Th 1 Ag，以协调Th 2应答的发展。以下 具体的目标是为了检验这一假设：具体的目标1）为了 描绘DC对溶酶体Ag（其诱导 Th 2应答）与其对Th 1 Ag的应答（例如，痤疮原杆菌）。 具体目的2）将暴露于溶酶体Ag后的DC表型与 这些抗原对Th 2应答的诱导作用，重点是可溶性 介质和共刺激信号。具体目标3）评估功能 DC在体内促进Ag注射后Th 1和Th 2应答的作用 在感染期间。我们将使用微阵列，蛋白质组学和消减cDNA 文库，以鉴定由银刺激的噬菌体特异性表达的基因。 DC，结合过继转移系统，其中DC用Ag脉冲， 体外和注射到小鼠中以检查鉴定的基因对Th 响应结果。将检查感染期间的DC活化， DC与其他免疫系统细胞的相互作用将使用 流式细胞术和免疫荧光显微术。长期目标是 更全面地了解DC在极化T细胞中的作用是一个重要的途径 为了改进疫苗接种或免疫治疗而启动反应 战略布局.

DESCRIPTION: (provided by the applicant): This is a revised, new application to examine the role of dendritic cells (DC) in the induction of Th2 responses to schistosome antigens. Initiation of the immune response to extracellular pathogens such as schistosomes occurs when DC present antigen (Ag) peptides to CD4+ T helper (Th) cells. This signal, along essential co-stimulatory signals from other DC surface molecules, promotes clonal expansion of T cells expressing relevant TCR. Thereafter the immune response focuses such that the majority of Th cells proceed to produce similar panels of effector cytokines. The outcome is usually an immune response dominated by Th1 or Th2 cells, where Th1 cells make IFN-g and IL-2, whereas Th2 cells make IL-4, -5, -6, -10 and -13. Expression of the transcription factors T-bet or GATA3 are respectively essential for acquisition of the Th1 or Th2 phenotype. IL-12 selects strongly for Th1 cells and IL-4 selects for Th2 cells. DC participates in Th1 by making IL-12 directly in response to certain microbial pathogens and upon ligation of CD40 by CD 154. However, little is known of the DC response to pathogens that induce Th2 responses. The hypothesis to be tested is that DC, by recognizing pathogen associated molecular patterns on schistosome Ag, respond in a way that is yet to be fully characterized, but which is distinct from their response to Th1 Ag, to orchestrate the development of a Th2 response. The following specific aims are designed to test this hypothesis: Specific Aim 1) To delineate the differences in the response of DC to schistosome Ag (which induce Th2 responses) versus their response to Th1 Ag (e.g., Propionebacterium acnes). Specific Aim 2) To link DC phenotype following exposure to schistosome Ag to the induction of Th2 responses by these Ag, with a focus on the role of soluble mediators and on co-stimulatory signals. Specific Aim 3) To assess the function of DC in promoting Th1 and Th2 responses in vivo following the injection of Ag and during infection. We will use micro-arrays, proteomics and subtractive cDNA libraries to identify genes expressed specifically by schistosome Ag-stimulated DC, combined with an adoptive transfer system in which DC are pulsed with Ag in vitro and injected into mice to examine the influence of identified genes on Th response outcome. DC activation during infection will be examined and the interaction of DC with other immune system cells will be investigated using flow cytometry and immunofluorescence microscopy. The long-term goal of this approach is to more fully understand the function of DC in polarized T cell response initiation with a view to improving vaccination or immuno-therapy strategies. .