Neuroprotective B Cell Immunotherapy for Contusion Traumatic Brain Injury

针对挫伤性脑损伤的神经保护 B 细胞免疫疗法

• 批准号: 10578748
• 负责人: Ruxandra F Sirbulescu
• 金额: $ 46.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578748
• 关键词: Address; Adopted; Affect; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antigen-Presenting Cells; Apoptosis; Axon; B cell therapy; B-Cell Antigen Receptor; B-Lymphocytes; Behavioral Paradigm; Biological Response Modifiers; Blood; Brain; Brain Injuries; Bromodeoxyuridine; CD19 gene; Cell Communication; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Therapy; Cells; Cellular immunotherapy; Central Nervous System; Clinical; Contusions; Data; Demyelinations; Environment; Flow Cytometry; Foundations; Gene Expression Profile; Gliosis; Histology; Histopathology; Homeostasis; Hour; Housekeeping; Immune; Immune system; Immunotherapy; In Situ; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injections; Injury; Interleukin-10; Interleukin-4; Investigation; Knock-out; Knockout Mice; Learning; Lesion; Macrophage; Maps; Mature B-Lymphocyte; Measures; Mediating; Medical; Memory impairment; Microglia; Modeling; Molecular; Mus; Myocardial Infarction; Neurodegenerative Disorders; Oxidative Stress; Pathway interactions; Patients; Pattern; Phenotype; Physiologic pulse; Plasma Cells; Play; Population; Positioning Attribute; Production; Proteomics; Publishing; Regulation; Research; Role; Sampling; Signal Transduction; Site; Skin wound healing; Sorting; Spleen; Symptoms; Therapeutic; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Transforming Growth Factor beta; Traumatic Brain Injury; Wound models; acute wound; axonal degeneration; brain parenchyma; cell growth; chronic wound; clinical development; conditional knockout; controlled cortical impact; cost effective; cytokine; efficacy testing; follow-up; functional restoration; glial activation; grasp; healing; humoral immunity deficiency; immune cell infiltrate; immunoregulation; improved outcome; injured; knockout gene; monocyte; motor learning; mouse model; neuronal survival; neuroprotection; neutrophil; novel; pathogen; peripheral blood; pre-clinical; protective effect; protein expression; receptor; repaired; response; response to injury; sensor; stroke model; transcriptome sequencing; wound; wound healing

ABSTRACT: In addition to antibody production, B lymphocytes are efficient regulators of the immune system both through direct cell-cell interactions and through secretion of soluble molecules. Recent investigations have underscored the beneficial role of anti-inflammatory (regulatory) B cells in the central nervous system (CNS), and shown that B cell depletion can worsen the symptoms of neurodegenerative diseases. We have demonstrated for the first time that exogenous B cells can be applied therapeutically to restore function in diverse injury models, including myocardial infarction, healing of acute and chronic wounds, and controlled cortical impact (CCI) traumatic brain injury (TBI). In our mouse CCI model a single injection of B cells to the brain parenchyma at the time of injury significantly reduced learning and memory deficits, reduced lesion volume by 40-60%, as well as gliosis and microglial activation at 35 days post-injury. Preliminary studies show that B cells administered as late as 6h after CCI remain equally effective in reducing motor learning deficits. Little is known about the mechanisms underlying the neuroprotective effects of B cells in TBI. Here, we propose to investigate the cellular and molecular mechanisms of B cell-mediated neuroprotection after CCI, ultimately positioning this novel cell-based therapy for clinical use in the context of contusion TBI. In Aim 1 we will assess at multiple time points the effect of intraparenchymal B cell administration on neuronal survival and axonal degeneration (1a), regulation of infiltrating immune cells (1b) and resident microglia (1c), and cell proliferation and differentiation at the injury site (1d). Based on preliminary mechanistic investigations of B cells in both wound healing and CCI, we hypothesize that naïve B cells placed at the site of CCI sense local inflammatory signals and damage- associated molecular patterns (DAMPs) via Toll-like receptor (TLR)- and B cell receptor (BCR)-dependent pathways, and adopt a regulatory phenotype. This cell state is associated with production of anti-inflammatory cytokines (including IL-10, but also IL-4, IL-35, and TGFβ), that act on adjacent infiltrating and resident (microglia) immune cells and bias their phenotype towards an anti-inflammatory, neuroprotective state. In Aim 2 we will interrogate the sensor and effector pathways that mediate the neuroprotective effects of B cells in a CCI model. Targeted gene knockout mouse models will be used to determine the involvement of key molecular pathways (TLR-dependent vs. CD19/BCR-dependent) in B cell environmental sensing at the injury site (2a) and to define key effector molecules required for mediating the B cell response to injury (2b). To investigate the role of microglia as down-stream mediators of inflammatory regulation via IL-10, we will modulate IL-10R expression on local microglia and test the efficacy of B cell treatment in the absence of responsive microglial partners (2c). Findings from the proposed studies will establish a foundation for clinical development of a novel, safe and cost- effective immune cell therapy to address TBI, a major unmet medical need.

摘要：除抗体产生外，B淋巴细胞是免疫系统的有效调节剂 通过直接细胞 - 细胞相互作用以及通过固体分子的分泌。最近的调查已有 强调抗炎（调节）B细胞在中枢神经系统（CNS）中的有益作用， 并表明B细胞耗竭会导致神经退行性疾病的症状。我们有 首次证明可以治疗外源B细胞恢复潜水员的功能 损伤模型，包括心肌梗塞，急性和慢性伤口的愈合以及受控的皮质 撞击（CCI）创伤性脑损伤（TBI）。在我们的小鼠CCI模型中，将B细胞单个注入到大脑 受伤时的实质大大减少了学习和记忆的定义，减少了病变的体积 伤害后35天，40-60％以及神经胶质细胞激活。初步研究表明B细胞 在CCI后至6小时的延迟在减少运动学习缺陷方面同样有效。鲜为人知 关于B细胞在TBI中神经保护作用的基础机制。在这里，我们建议调查 CCI后B细胞介导的神经保护的细胞和分子机制，最终将其定位 在挫伤TBI的背景下，基于新型的细胞疗法用于临床使用。在AIM 1中，我们将多次评估 指出了核内B细胞给药对神经元存活和轴突变性（1A）的影响， 调节浸润免疫细胞（1B）和居民小胶质细胞（1C），以及细胞增殖和分化 伤害部位（1D）。基于伤口愈合和CCI中B细胞的初步机械研究， 我们假设将幼稚的B细胞放置在CCI所在的位置，感知局部炎症信号和损害 - 通过Toll-like受体（TLR）和B细胞受体（BCR）依赖性的相关分子模式（潮湿） 途径，并采用调节表型。该细胞状态与抗炎的产生有关 细胞因子（包括IL-10，以及IL-4，IL-35和TGFβ），作用于相邻浸润和居民（小胶质细胞） 免疫细胞并将其表型偏向抗炎，神经保护状态。在目标2中，我们将 询问介导CCI模型中B细胞神经保护作用的传感器和效应途径。 靶向基因敲除小鼠模型将用于确定关键分子途径的参与 （在损伤部位（2A）的B细胞环境传感中，（依赖TLR依赖与CD19/BCR依赖性）并定义 介导B细胞对损伤的反应所需的关键效应分子（2B）。调查 小胶质细胞作为通过IL-10进行炎症调节的下游介质，我们将调节IL-10R表达 在局部小胶质细胞上并在没有反应性小胶质伴侣（2C）的情况下测试B细胞处理的效率。 拟议研究的发现将为新颖，安全和成本的临床发展奠定基础 有效的免疫细胞疗法以解决TBI，这是一种主要的未满足医疗需求。