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中文摘要
翻译
人体需要NK细胞来杀死病毒感染的细胞。NK介导的病毒免疫与 先天性细胞因子(如I型干扰素),持续的树突状细胞和加速获得病毒特异性 受感染动物的效应T细胞。然而,很少有人知道如何有效的NK介导的病毒免疫 可以调节和塑造其他免疫细胞的成熟和/或活化特征。该提案基于 两种重组同源株中MHC调控下NK介导病毒免疫的新遗传模型 被称为R2和R7的小鼠。R2和R7在MHC I类D亚区仅相差约300-kb,但 NK介导的病毒免疫在R7小鼠中是显著的。本研究项目的广泛长期目标 试图研究如何有效的NK介导的病毒免疫可以赋予免疫细胞显着的控制, 除了它们在先天免疫中的关键功能外,还通过受控的遗传比较。指导 假设R2和R7中NK介导病毒控制差异将与适应性细胞的诱导有关, 在病毒水平显著不同之前,通过调节细胞因子的精细平衡来增强免疫力。三个具体 目标:目标1。确定MHC调节的NK细胞功能对诱导和 CD 8 + T细胞对MCMV感染的反应动力学。将在流程中评估R2和R7的CD 8 + CTL 细胞计数和细胞毒性测定,以确定诱导时间过程、响应幅度、激活状态 和感染后的效应子活性。用CD 8 + TCR转基因T细胞的连续转移将进一步定义免疫应答。 诱导和效应活性CDS T细胞在抗性和易感小鼠的脾脏中应答。目的 2.分析NK细胞-DC相互作用对脾NK细胞功能的影响。脾的激活状态 在R2和R7感染后,NK细胞和CD 11 c + DC的频率和亚群分布将被检测。 使用流式细胞术分析。脾细胞因子的产生,特别是1型干扰素和IL-10,将被抑制。 通过多重细胞因子测定进行评价。目标3。研究IL-10在MHC中的潜在因果作用 调节NK细胞介导的病毒免疫力的差异。IL-10对细胞凋亡的潜在调节作用 将在IL-10 GFP敲入报告小鼠和IL-10缺陷小鼠中评价适应性免疫的诱导
英文摘要
NK cells are needed in the body to kill virus infected cells. NK-mediated virus immunity has been linked with innate cytokines (e.g. type I interferons), sustained dendritic cells and accelerated acquisition of virus specific effector T cells in infected animals. However, little is known about how efficient NK-mediated virus immunity can regulate and shape maturation and/or activation profiles of other immune cells. This proposal is based on a new genetic model for NK-mediated virus immunity under MHC control in two recombinant congenic strains of mice referred to as R2 and R7. R2 and R7 only differ by ~300-kb in the MHC class I D subregion, but NK-mediated virus immunity is remarkable in R7 mice. The broad long-term objective for this research project seeks to examine how efficient NK-mediated virus immunity can impart dramatic control over immune cells, in addition to their critical function in innate immunity, through controlled genetic comparisons. A guiding hypothesis is that NK-mediated virus control differences in R2 and R7 will be linked with induction of adaptive immunity through regulation of a fine balance of cytokines before virus levels differ significantly. Three specific aims are proposed: Aim 1. To determine the effect of MHC regulated NK cell function on the induction and kinetics of the CD8+ T cell response to MCMV infection. CD8+ CTLs from R2 and R7 will be assessed in flow cytometric and cytotoxicity assays to ascertain the induction time course, response magnitude, activation state and effector activity after infection. Adoptive transfers with CD8+ TCR transgenic T-cells will further define the induction and the effector activity CDS T cells responding in the spleens of resistant and susceptible mice. Aim 2. To analyze the effect of NK cell-DC interactions on splenic NK cell function. Activation states for splenic NK cells and the frequency and subset distribution of CDllc+ DCs after infection of R2 and R7 will be analyzed using flow cytometry. Splenic cytokine production, especially type 1 interferon and IL-10, will be evaluated via multiplex cytokine assays. Aim 3. To examine a potential causal role for IL-10 underlying MHC regulated differences in NK cell-mediated virus immunity. A potential regulatory role for IL-10 on the induction of adaptive immunity will be evaluated in IL10GFP knock-in reporter mice and IL-10 deficient mice
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Genetic basis of secondary lymphoid organ protection after virus infection
  • 批准号:
    8987720
  • 项目类别:
  • 资助金额:
    $23.4万
  • 财政年份:
    2015
  • 负责人:
    Michael G Brown
  • 依托单位:
MHC regulation of NK cell mediated virus immunity
  • 批准号:
    7987843
  • 项目类别:
  • 资助金额:
    $38.28万
  • 财政年份:
    2010
  • 负责人:
    Michael G Brown
  • 依托单位:
MHC regulation of NK cell mediated virus immunity
  • 批准号:
    8115983
  • 项目类别:
  • 资助金额:
    $37.9万
  • 财政年份:
    2010
  • 负责人:
    Michael G Brown
  • 依托单位:
MHC regulation of NK cell mediated virus immunity
  • 批准号:
    8508172
  • 项目类别:
  • 资助金额:
    $35.63万
  • 财政年份:
    2010
  • 负责人:
    Michael G Brown
  • 依托单位:
海外基金