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: 10211304
• 负责人: Ruxandra F Sirbulescu
• 金额: $ 43.01万
• 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/10211304
• 关键词: Address; Adopted; Affect; Anti-Inflammatory Agents; Antibodies; Antibody Formation; Antigen Presentation; 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; 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; Lead; Learning; Lesion; Maps; Mature B-Lymphocyte; Measures; Mediating; Medical; Memory impairment; Microglia; Modeling; Molecular; Mus; Myocardial Infarction; Neuraxis; Neurodegenerative Disorders; Oxidative Stress; Pathway interactions; Patients; Pattern; Phenotype; Physiologic pulse; Plasma Cells; Play; Population; Positioning Attribute; Production; Proliferating; Proteomics; Publishing; Receptor Cell; Regulation; Research; Role; Sampling; Signal Transduction; Site; Skin wound healing; Spleen; Structure; Symptoms; Therapeutic; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Transforming Growth Factor beta; Traumatic Brain Injury; Tumor-infiltrating immune cells; Wound models; acute wound; axonal degeneration; base; brain parenchyma; cell growth; chronic wound; clinical development; conditional knockout; controlled cortical impact; cost effective; cytokine; efficacy testing; follow-up; functional restoration; grasp; healing; immunoregulation; improved outcome; injured; knockout gene; macrophage; 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：除了产生抗体外，B淋巴细胞也是免疫系统的有效调节者 通过直接的细胞-细胞相互作用和通过可溶性分子的分泌。最近的调查 强调了抗炎（调节）B细胞在中枢神经系统（CNS）中的有益作用， 并表明B细胞缺失会使神经退行性疾病的症状恶化。我们有 首次证明了外源性B细胞可以在治疗上用于恢复多种疾病的功能， 损伤模型，包括心肌梗死、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，向大脑单次注射B细胞 损伤时的软组织显著减少了学习和记忆缺陷， 40 - 60%，以及损伤后35天的神经胶质增生和小胶质细胞活化。初步研究表明B细胞 在CCI后6小时给药仍然同样有效地减少运动学习缺陷。知之甚少 关于B细胞在TBI中的神经保护作用的机制。在这里，我们建议调查 CCI后B细胞介导的神经保护作用的细胞和分子机制，最终将其定位于 用于挫伤TBI背景下的临床使用的新型基于细胞的疗法。在目标1中，我们将在多个时间评估 点实质内B细胞给药对神经元存活和轴突变性的影响（1a）， 浸润免疫细胞（1b）和驻留小胶质细胞（1c）的调节，以及细胞增殖和分化， 损伤部位（1d）。基于B细胞在伤口愈合和CCI中的初步机制研究， 我们假设放置在CCI部位的幼稚B细胞感知局部炎症信号和损伤- 通过Toll样受体（TLR）和B细胞受体（BCR）依赖的相关分子模式（DAMP） 途径，并采用调节表型。这种细胞状态与抗炎物质的产生有关。 细胞因子（包括IL-10，但也包括IL-4、IL-35和TGF β），作用于邻近浸润和驻留（小胶质细胞） 免疫细胞并使其表型偏向于抗炎、神经保护状态。在目标2中， 询问CCI模型中介导B细胞神经保护作用的传感器和效应器途径。 靶向基因敲除小鼠模型将用于确定关键分子通路的参与 （TLR依赖性vs. CD 19/BCR依赖性）在损伤部位B细胞环境感知中的作用（2a），并确定 介导B细胞对损伤应答所需的关键效应分子（2B）。调查的作用 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的表达 并测试在不存在应答性小胶质细胞伴侣的情况下B细胞治疗的功效（2c）。 拟议研究的结果将为临床开发一种新的、安全的、低成本的药物奠定基础。 有效的免疫细胞疗法，以解决TBI，一个主要的未满足的医疗需求。