ROLE OF B CELL ANTIGEN PRESENTATION IN AUTOIMMUNE ENCEPHALOMYELITIS

B 细胞抗原呈递在自身免疫性脑脊髓炎中的作用

基本信息

  • 批准号:
    8849513
  • 负责人:
  • 金额:
    $ 33.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-01 至 2016-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-dependent model for the human disease multiple (MS). Several antigen presenting cells (APCs) coordinate and regulate CD4 T cell function during immune responses. B cells likely have multiple roles in the pathogenesis of MS, with their capacity to function as APCs and drive auto-reactive CD4 T cell responses gaining more recognition. However, questions remain as to the importance of antigen presentation in the role for B cells in EAE and MS. We have designed a new tool in which individual subsets of APCs are capable of conditionally expressing MHCII in vivo. We successfully targeted a stop sequence flanked by loxP sites to the MHCII ¿ chain locus in mice in order to utilize the Cre/loxP system for conditional expression of MHCII. Successful conditional manipulation was achieved using B lineage-specific Cre mice, restricting expression of MHCII to B cells. B cell expression of MHCII alone was sufficient to support inflammatory demyelination of the central nervous system (CNS) mediated by encephalitogenic CD4 T cells, but only when B cells were highly efficient at recognizing target antigen. Based on these observations, we hypothesize that the process by which B cells coordinate antigen- specific CD4 T cell autoimmune destruction of myelin is dependent upon B cell localization to the CNS and efficient capture of target antigen during the propagation of EAE. We aim to: 1) Determine the requirement for antigen-specific humoral responses during EAE mediated by B cell antigen presentation; 2) Determine the requirement for B cell antigen presentation in the CNS compartment during EAE; and 3) Determine the effect of B cell depletion on dendritic cell (DC) antigen presentation in EAE and MS. While the proposal herein utilizes a novel system to explore the role of B cell antigen presentation during EAE, this powerful murine genetic system is optimally designed to investigate the cellular contributions by various APCs in different models of immunity and autoimmunity. Furthermore, studies pursuing functional alterations in DCs from MS patients receiving B cell depletion therapy will bring into context the relation between antigen specific B cell regulation of CD4 T cell function and B cell therapies used to treat patients with MS. These studies will provide mechanistic understanding of immune regulation by B cells in MS and offer potential for future design of optimal B cell and CD4 T cell therapeutics.
描述(由申请人提供):实验性自身免疫性脑脊髓炎(EAE)是人类多发性疾病(MS)的CD 4 T细胞依赖性模型。几种抗原呈递细胞(APC)在免疫应答期间协调和调节CD 4 T细胞功能。B细胞可能在MS的发病机制中具有多种作用,其作为APC和驱动自身反应性CD 4 T细胞应答的能力得到更多的认可。然而,问题仍然存在的重要性,抗原呈递的B细胞在EAE和MS的作用。我们已经设计了一种新的工具,其中个别亚群的APC能够有条件地表达MHCII在体内。为了利用Cre/loxP系统进行MHCII的条件表达,我们成功地将侧接loxP位点的终止序列靶向小鼠中的MHCII?链基因座。使用B谱系特异性Cre小鼠实现成功的条件操作,将MHCII的表达限制于B细胞。单独的MHCII的B细胞表达足以支持由致脑炎性CD 4 T细胞介导的中枢神经系统(CNS)的炎性脱髓鞘,但仅当B细胞在识别靶抗原方面是高效的时。基于这些观察结果,我们假设B细胞协调抗原特异性CD 4 T细胞自身免疫性破坏髓鞘的过程依赖于B细胞定位于CNS和在EAE增殖期间有效捕获靶抗原.我们的目标是:1)确定在由B细胞抗原呈递介导的EAE期间抗原特异性体液应答的需要; 2)确定在EAE期间CNS隔室中B细胞抗原呈递的需要;和3)确定B细胞去除对树突状细胞(DC)的影响EAE和MS中的抗原呈递。虽然本文的建议利用新的系统来探索B细胞抗原呈递在EAE期间的作用,这种强大的鼠遗传系统被最佳地设计用于研究不同免疫和自身免疫模型中各种APC的细胞贡献。此外,研究寻求从接受B细胞耗竭疗法的MS患者的DC中的功能改变将使CD 4 T细胞功能的抗原特异性B细胞调节与用于治疗MS患者的B细胞疗法之间的关系进入上下文。这些研究将提供MS中B细胞的免疫调节的机制理解,并为未来设计最佳B细胞和CD 4 T细胞疗法提供潜力。

项目成果

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Gregory Wu其他文献

Gregory Wu的其他文献

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{{ truncateString('Gregory Wu', 18)}}的其他基金

Role of CSF microglia in health and disease
脑脊液小胶质细胞在健康和疾病中的作用
  • 批准号:
    10367573
  • 财政年份:
    2022
  • 资助金额:
    $ 33.25万
  • 项目类别:
Role of CSF microglia in health and disease
脑脊液小胶质细胞在健康和疾病中的作用
  • 批准号:
    10651623
  • 财政年份:
    2022
  • 资助金额:
    $ 33.25万
  • 项目类别:
The Role of TRPV4 in central nervous system immunity and disease
TRPV4在中枢神经系统免疫和疾病中的作用
  • 批准号:
    10000177
  • 财政年份:
    2018
  • 资助金额:
    $ 33.25万
  • 项目类别:
The Role of TRPV4 in central nervous system immunity and disease
TRPV4在中枢神经系统免疫和疾病中的作用
  • 批准号:
    10240568
  • 财政年份:
    2018
  • 资助金额:
    $ 33.25万
  • 项目类别:
ROLE OF B CELL ANTIGEN PRESENTATION IN AUTOIMMUNE ENCEPHALOMYELITIS
B 细胞抗原呈递在自身免疫性脑脊髓炎中的作用
  • 批准号:
    8687759
  • 财政年份:
    2013
  • 资助金额:
    $ 33.25万
  • 项目类别:
ROLE OF B CELL ANTIGEN PRESENTATION IN AUTOIMMUNE ENCEPHALOMYELITIS
B 细胞抗原呈递在自身免疫性脑脊髓炎中的作用
  • 批准号:
    9292390
  • 财政年份:
    2013
  • 资助金额:
    $ 33.25万
  • 项目类别:
ROLE OF B CELL ANTIGEN PRESENTATION IN AUTOIMMUNE ENCEPHALOMYELITIS
B 细胞抗原呈递在自身免疫性脑脊髓炎中的作用
  • 批准号:
    9084683
  • 财政年份:
    2013
  • 资助金额:
    $ 33.25万
  • 项目类别:
ROLE OF B CELL ANTIGEN PRESENTATION IN AUTOIMMUNE ENCEPHALOMYELITIS
B 细胞抗原呈递在自身免疫性脑脊髓炎中的作用
  • 批准号:
    8559606
  • 财政年份:
    2013
  • 资助金额:
    $ 33.25万
  • 项目类别:
T cell regulation by dendritic cells in EAE
EAE 中树突状细胞对 T 细胞的调节
  • 批准号:
    8097296
  • 财政年份:
    2008
  • 资助金额:
    $ 33.25万
  • 项目类别:
T cell regulation by dendritic cells in EAE
EAE 中树突状细胞对 T 细胞的调节
  • 批准号:
    7588318
  • 财政年份:
    2008
  • 资助金额:
    $ 33.25万
  • 项目类别:

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