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: 8509042
• 负责人: Halina Offner
• 金额: $ 35.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8509042
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; B-Lymphocyte Subsets; B-Lymphocytes; Blood; Brain; Brain Injuries; Brain Ischemia; CD19 gene; CD22 gene; Cause of Death; Cell Count; Cell Therapy; Cells; Cerebral Ischemia; Cerebral hemisphere; Clinical; Contralateral; Corpus striatum structure; Data; Disease; Employee Strikes; Event; Experimental Models; Frequencies; Human; Immune; Immune system; Infarction; Infection; Inflammation; Inflammatory; Interleukin-10; Ipsilateral; Ischemic Stroke; Ligands; Lymphocyte Depletion; Lymphoid Tissue; Mediating; Middle Cerebral Artery Occlusion; Modeling; Multiple Sclerosis; Mus; Organ; Outcome; Pathology; Pathway interactions; Patients; Peripheral; Receptor Activation; Rodent; Rodent Model; Role; Severity of illness; Spleen; Stroke; Systemic disease; Thymus Gland; Time; United States; Wild Type Mouse; acute stroke; base; central nervous system injury; cytokine; design; disability; functional outcomes; immune depression; improved; injured; nervous system disorder; neurotoxic; novel; receptor; reconstitution; restoration; theories

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产生IL-10的CD1DHICD5+调节性B淋巴细胞（B10）的一个少量但强大的子集，该淋巴细胞（B10）可以限制CNS炎症和啮齿动物模型中神经疾病的临床迹象。在此多PI应用中，我们假设内源性调节B细胞（包括B10子集）通过控制中枢神经系统和外周免疫器官在局灶性中触发的免疫介导的炎症来限制MCAO中的梗死大小。此外，我们预测，B10细胞的选择性诱导或被动转移，以增强B10细胞频率将提供野生型（WT）小鼠的额外调节作用，并导致梗死和改善的功能性中风结果。该应用的目的是：1）确定B淋巴细胞耗竭和调节性B10细胞恢复和治疗对MCAO后脾脏和脑半球的梗死大小，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小鼠维持更大的组织学损害和功能性差。我们将确定负责的B细胞亚群，包括分泌IL-10的B10子集。 2）评估脾和脑中PD-1/PD-L负共激活途径对梗塞大小，免疫细胞组成和炎症特征的贡献。假设是，该受体配体途径在B淋巴细胞（尤其是CD1DHICD5+ B细胞）中的激活改变了MCAO的结果。 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）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，尤其是CD1DHICD5+ B调节细胞，通过抑制小胶质细胞激活，通过分泌因子或直接的细胞 - 细胞接触来改善缺血后的结果，从而实现PD-1负共激活机制。具体而言，此目标将评估PD-L+ CD19+ B细胞或产生IL-10的CD1DHICD5+ B-REG细胞和活化的PD-1+ Mg之间的相互作用。拟议的研究凭借其依据：1）完全新颖性，2）专注于精选B细胞子集的炎症调节能力和3）急性中风中调节B细胞治疗的能力。