Regulatory B-cells Limit CNS Inflammation and Infarct in Experimental Stroke

调节性 B 细胞限制实验性中风中的中枢神经系统炎症和梗塞

基本信息

  • 批准号:
    8509042
  • 负责人:
  • 金额:
    $ 35.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-15 至 2016-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Recent studies have identified a small but powerful subset of IL-10-producing CD1dhiCD5+ regulatory B lymphocytes (B10) that can limit CNS inflammation and clinical signs of neurological disease in rodent models. In this multi-PI application, we hypothesize that endogenous regulatory B-cells, including the B10 subset, limit infarct size in MCAO by controlling immune-mediated inflammation triggered both in the CNS and in peripheral immune organs by focal stroke. Further, we predict that either selective induction or passive transfer of B10 cells so as to augment B10 cell frequency will provide additional regulatory effects in wild type (WT) mice, and result in smaller infarct and improved functional stroke outcome. The aims of this application are: 1) Determine the effects of B lymphocyte depletion and regulatory B10 cell restoration and treatment on infarct size, immune cellular composition and inflammatory signature in both spleen and brain hemispheres after MCAO. The hypothesis is that B cell KO mice sustain larger histological damage and poor functional outcome than do WT mice. We will determine the responsible B-cell subpopulations, including the IL-10-secreting B10 subset. 2) Evaluate the contribution of the PD-1/PD-L negative co-activation pathway to infarct size, immune cell composition and inflammatory signature in spleen and brain. The hypothesis is that activation of this receptor-ligand pathway in B lymphocytes, particularly CD1dhiCD5+ B-cells, alters outcomes from MCAO. This aim will evaluate PD-1, PD-L1 and PD-L2 expression on B-cells, confirm our preliminary findings of increased infarct size in PD-1 KO mice, extend the analysis to PD-L1 and PD-L2 KO mice, and evaluate the contribution of B10- cells to the PD-1/PD-L negative co-activation after stroke by reconstituting PD-L KO mice with WT B10-cells. 3) Evaluate the mechanisms through which B-cells inhibit microglial (MG) activation and release of neurotoxic factors. The hypothesis is that B cells, particularly CD1dhiCD5+ B regulatory cells, improve post-ischemic outcomes by suppressing microglial activation, either via secreted factors or direct cell-cell contact that enables a PD-1 negative co-activation mechanism. Specifically, this aim will evaluate interaction between PD-L+ CD19+ B-cells or IL-10-producing CD1dhiCD5+ B-reg cells and activated PD-1+ MG. The proposed studies offer high impact for the stroke field by virtue of their: 1) complete novelty, 2) focus on the inflamma-suppressive regulatory capacity of select B-cell subsets and 3) ability to lay translational groundwork for regulatory B-cell therapy in acute stroke.
描述(由申请人提供):最近的研究已经确定了一个小但强大的产生il -10的CD1dhiCD5+调节性B淋巴细胞(B10)亚群,可以在啮齿动物模型中限制中枢神经系统炎症和神经系统疾病的临床症状。在这个多pi应用中,我们假设内源性调节性b细胞,包括B10亚群,通过控制局灶性中风在中枢神经系统和外周免疫器官引发的免疫介导炎症来限制MCAO梗死面积。此外,我们预测B10细胞的选择性诱导或被动转移以增加B10细胞频率将在野生型(WT)小鼠中提供额外的调节作用,并导致较小的梗死和改善功能性卒中结局。本应用的目的是:1)确定B淋巴细胞耗损和调节性B10细胞恢复和治疗对MCAO后脾和脑半球梗死面积、免疫细胞组成和炎症特征的影响。假设是B细胞KO小鼠比WT小鼠承受更大的组织学损伤和更差的功能预后。我们将确定负责的b细胞亚群,包括分泌il -10的B10亚群。2)评价PD-1/PD-L阴性共激活通路对脾和脑梗死面积、免疫细胞组成和炎症特征的贡献。假设是B淋巴细胞,特别是CD1dhiCD5+ B细胞中这种受体-配体途径的激活,改变了MCAO的结果。本研究将评估PD-1、PD-L1和PD-L2在b细胞上的表达,证实我们在PD-1 KO小鼠中梗死面积增加的初步发现,将分析扩展到PD-L1和PD-L2 KO小鼠,并通过用WT B10细胞重构PD-L KO小鼠来评估B10-细胞对中风后PD-1/PD-L阴性共激活的贡献。3)评估b细胞抑制小胶质细胞(MG)激活和神经毒性因子释放的机制。假设是B细胞,特别是CD1dhiCD5+ B调节细胞,通过分泌因子或直接细胞-细胞接触实现PD-1负共激活机制,通过抑制小胶质细胞激活来改善缺血后的结果。具体来说,该目的将评估PD-L+ CD19+ b细胞或产生il -10的CD1dhiCD5+ B-reg细胞与活化的PD-1+ MG之间的相互作用。所提出的研究具有以下特点:1)完全新颖,2)专注于选定b细胞亚群的炎症抑制调节能力,3)能够为急性卒中调节性b细胞治疗奠定翻译基础,因此对卒中领域具有重要影响。

项目成果

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Halina Offner其他文献

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{{ truncateString('Halina Offner', 18)}}的其他基金

Compensatory mechanisms of estrogen mediated protection from EAE in IL-10 KO mice
IL-10 KO 小鼠雌激素介导的 EAE 保护的补偿机制
  • 批准号:
    10263144
  • 财政年份:
    2020
  • 资助金额:
    $ 35.35万
  • 项目类别:
Estrogen-Induced Regulatory B Cells Protect Against EAE & Limit CNS Inflammation
雌激素诱导的调节性 B 细胞可预防 EAE
  • 批准号:
    8660356
  • 财政年份:
    2013
  • 资助金额:
    $ 35.35万
  • 项目类别:
Estrogen-Induced Regulatory B Cells Protect Against EAE & Limit CNS Inflammation
雌激素诱导的调节性 B 细胞可预防 EAE
  • 批准号:
    8558759
  • 财政年份:
    2013
  • 资助金额:
    $ 35.35万
  • 项目类别:
Estrogen-Induced Regulatory B Cells Protect Against EAE & Limit CNS Inflammation
雌激素诱导的调节性 B 细胞可预防 EAE
  • 批准号:
    8851694
  • 财政年份:
    2013
  • 资助金额:
    $ 35.35万
  • 项目类别:
Estrogen-Induced Regulatory B Cells Protect Against EAE & Limit CNS Inflammation
雌激素诱导的调节性 B 细胞可预防 EAE
  • 批准号:
    9293408
  • 财政年份:
    2013
  • 资助金额:
    $ 35.35万
  • 项目类别:
Estrogen-Induced Regulatory B Cells Protect Against EAE & Limit CNS Inflammation
雌激素诱导的调节性 B 细胞可预防 EAE
  • 批准号:
    9068255
  • 财政年份:
    2013
  • 资助金额:
    $ 35.35万
  • 项目类别:
Sex differences in brain inflammation in experimental stroke
实验性脑卒中脑部炎症的性别差异
  • 批准号:
    8629805
  • 财政年份:
    2012
  • 资助金额:
    $ 35.35万
  • 项目类别:
Regulatory B-cells Limit CNS Inflammation and Infarct in Experimental Stroke
调节性 B 细胞限制实验性中风中的中枢神经系统炎症和梗死
  • 批准号:
    8186316
  • 财政年份:
    2011
  • 资助金额:
    $ 35.35万
  • 项目类别:
Regulatory B-cells Limit CNS Inflammation and Infarct in Experimental Stroke
调节性 B 细胞限制实验性中风中的中枢神经系统炎症和梗塞
  • 批准号:
    8690181
  • 财政年份:
    2011
  • 资助金额:
    $ 35.35万
  • 项目类别:
Regulatory B-cells Limit CNS Inflammation and Infarct in Experimental Stroke
调节性 B 细胞限制实验性中风中的中枢神经系统炎症和梗死
  • 批准号:
    8320086
  • 财政年份:
    2011
  • 资助金额:
    $ 35.35万
  • 项目类别:

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