Dendritic cell function in schistosomiasis

描述：(由申请人提供)：这是一份修订后的新申请 检测树突状细胞(DC)在诱导Th2应答中的作用 血吸虫抗原。启动对细胞外的免疫反应 当DC将抗原(Ag)肽递送到 CD4+T辅助细胞(Th)。这一信号与基本的共刺激信号一起 来自其他DC表面分子，促进T细胞的克隆性增殖 表达相应的TCR。此后，免疫反应集中在这样的地方 大多数Th细胞继续产生类似的效应性细胞因子。 结果通常是由Th1或Th2细胞主导的免疫反应，其中 Th1细胞产生干扰素-g和IL-2，而Th2细胞产生IL-4、-5、-6、-10和 -13.转录因子T-bet和GATA3的表达 对于获得Th1或Th2表型是必不可少的。IL-12强烈选择 Th1细胞和IL-4选择Th2细胞。DC通过制作 IL-12对某些微生物病原体的直接反应和在结扎 CD40由CD 154提供。然而，对DC对病原体的反应知之甚少 诱导Th2反应。需要检验的假设是DC，通过认识到 血吸虫Ag上病原体相关分子模式的反应方式 尚未得到充分的表征，但这与他们对 Th1抗原，以协调Th2反应的发展。以下是 具体目标旨在检验这一假设：具体目标1) 描述树突状细胞对血吸虫抗原反应的差异 Th2应答)和Th1抗原应答(如痤疮原杆菌)。 特定目的2)将血吸虫抗原暴露后的DC表型与 这些抗原诱导Th2应答，重点是可溶性抗原的作用 调停者和共刺激信号。具体目标3)评估功能 树突状细胞促进体内注射抗原后Th1和Th2应答的研究 在感染期间。我们将使用微阵列、蛋白质组学和消减cdna 鉴定血吸虫抗原刺激特异性表达基因的文库 DC与过继转移系统相结合，在该系统中DC被脉冲地注入Ag 体外和注射小鼠以检测已识别的基因对Th的影响 响应结果。将检查感染期间DC的激活情况，并 树突状细胞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镜。这样做的长期目标是 途径是更全面地了解DC在极化T细胞中的作用 为改进疫苗接种或免疫治疗而发起的反应 战略。。

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. .