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

基本信息

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
项目类别：
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

项目摘要

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 淋巴细胞还是免疫系统的有效调节者最近的研究表明，通过直接的细胞间相互作用和可溶性分子的分泌。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 细胞耗竭会使神经退行性疾病的症状恶化。首次将外源 B 细胞应用于治疗以恢复多种疾病的功能损伤模型，包括心肌梗塞、急性和慢性伤口的愈合以及控制性皮质损伤在我们的小鼠 CCI 模型中，将 B 细胞注射到大脑中。损伤时的实质显着减少了学习和记忆缺陷，减少了病变体积 40-60%，以及损伤后 35 天的神经胶质细胞增生和小胶质细胞活化。最迟在 CCI 后 6 小时施用对于减少运动学习缺陷仍然同样有效。关于 TBI 中 B 细胞神经保护作用的机制，我们建议进行研究。 CCI 后 B 细胞介导的神经保护的细胞和分子机制，最终定位了这一点在目标 1 中，我们将多次评估用于临床挫伤 TBI 的新型细胞疗法。指出实质内 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) 和常驻小胶质细胞 (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，我们研究发现，放置在 CCI 部位的幼稚 B 细胞能够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，并采取调节表型，这种细胞状态与抗炎物质的产生有关。细胞因子（包括 IL-10、IL-4、IL-35 和 TGFβ），作用于邻近浸润和驻留细胞（小胶质细胞）在目标 2 中，我们将调整免疫细胞并将其表型偏向于抗炎、神经保护状态。探究 CCI 模型中介导 B 细胞神经保护作用的传感器和效应器通路。靶向基因敲除小鼠模型将用于确定关键分子途径的参与（TLR 依赖性与 CD19/BCR 依赖性）在损伤部位的 B 细胞环境传感中 (2a) 并定义介导 B 细胞对损伤的反应所需的关键效应分子 (2b)。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 表达局部小胶质细胞并测试在没有反应性小胶质细胞伙伴的情况下 B 细胞治疗的功效 (2c)。拟议研究的结果将为临床开发新型、安全且成本低廉的药物奠定基础。有效的免疫细胞疗法可解决 TBI 这一未满足的重大医疗需求。