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
• 负责人: Halina Offner
• 金额: $ 37.38万
• 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/8320086
• 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一小部分但功能强大的产生IL-10的CD 1 dhiCD 5+调节性B淋巴细胞（B10）子集，可以限制啮齿动物模型中的中枢神经系统炎症和神经系统疾病的临床体征。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，通过控制局灶性卒中在CNS和外周免疫器官中触发的免疫介导的炎症来限制MCAO中的梗死面积。此外，我们预测，无论是选择性诱导或被动转移B10细胞，以增加B10细胞的频率将提供额外的调节作用，在野生型（WT）小鼠，并导致较小的梗死和改善功能性中风的结果。本申请的目的是：1）确定B淋巴细胞耗竭和调节性B10细胞恢复和治疗对MCAO后脾和脑半球中的梗死面积、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较差的功能结果。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阴性共活化途径对脾和脑中梗死面积、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CD 1 dhiCD 5 + B细胞中受体-配体途径的激活改变了MCAO的结果。该目的将评估B细胞上的PD-1、PD-L1和PD-L2表达，证实我们在PD-1 KO小鼠中梗死面积增加的初步发现，将分析扩展至PD-L1和PD-L2 KO小鼠，并通过用WT B10细胞重建PD-L KO小鼠来评估B10细胞对卒中后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CD 1 dhiCD 5 + B调节细胞，通过抑制小胶质细胞活化改善缺血后结果，通过分泌因子或直接细胞-细胞接触实现PD-1阴性共活化机制。具体而言，该目的将评价PD-L+ CD 19 + B细胞或产生IL-10的CD 1dhiCD 5 + B-reg细胞与活化的PD-1+ MG之间的相互作用。拟议的研究由于其以下特点对卒中领域产生了很大影响：1）完全新奇，2）关注选定B细胞亚群的炎症抑制调节能力，3）为急性卒中中的调节性B细胞治疗奠定转化基础的能力。