Assessing the neuroprotective effect of B cell-therapy after intracerebral hemorrhage

评估脑出血后 B 细胞疗法的神经保护作用

基本信息

批准号：
10456264
负责人：
Ruxandra F Sirbulescu
金额：
$ 8.31万
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：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456264
关键词：
Adopted Affect Alzheimer&apos s Disease Anti-Inflammatory Agents Antibodies Antibody Formation Anticoagulation Antigen Presentation Anxiety Apoptosis Autologous B cell therapy B-Lymphocytes Biological Models Biological Response Modifiers Blood Blood - brain barrier anatomy Brain Catheters Cell Communication Cell Proliferation Cell Therapy Cells Cerebral hemisphere hemorrhage Chronic Clinical Clinical Trials Coagulation Process Cognitive Cognitive deficits Contusions Craniotomy Data Dementia Dose Environment Excision Experimental Models Gliosis Goals HLA Antigens Hematoma Hemostatic function Hour Immune system Inflammation Injections Injury Interleukin-10 Interleukin-4 Intravenous Intravenous infusion procedures Intraventricular Investigation Iron Chelation Ischemic Brain Injury Ischemic Stroke Knock-out Learning Lesion Leukapheresis Mature B-Lymphocyte Mediating Memory impairment Middle Cerebral Artery Occlusion Modeling Molecular Motor Mus Myocardial Myocardial Infarction Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurological outcome Neurosurgeon Onset of illness Operating Rooms Outcome Oxidative Stress Patients Persons Phenotype Play Proteomics Publishing Recovery Reporting Reproducibility Role Site Standardization Stroke Survivors Symptoms Testing Therapeutic Time Tissues Toll-Like Receptor Pathway Toll-like receptors Transforming Growth Factor beta Translating Traumatic Brain Injury acute wound base blood pressure control brain parenchyma cell growth central nervous system injury chronic wound clinical application clinically relevant collagenase controlled cortical impact cytokine design functional outcomes functional restoration grasp immunomodulatory therapies immunoregulation improved injured macrophage morris water maze mortality motor learning mouse model neuroinflammation neuron loss neutrophil novel peripheral blood pre-clinical prevent protective effect protein expression repaired stroke model systemic inflammatory response thrombolysis tissue repair translational impact wound wound healing

项目摘要

ABSTRACT: Intracerebral hemorrhage (ICH) comprises approximately 15% of strokes affecting 2 million people per year worldwide with up to 70% mortality by 5 years; less than 40% of survivors function independently at 3 months. Treatment for ICH is supportive, with emphasis on reversal of anticoagulation and limiting hematoma expansion by blood pressure control and adequate hemostasis. Currently, no specific treatment exists to improve neurological outcome in ICH survivors, making therapy for ICH a critical unmet need. We have recently shown the utility and efficacy of a novel cell-based immunomodulatory therapy, based on B cells, to accelerate tissue repair in the periphery and protect from neurodegenerative effects after central nervous system (CNS) injury. 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 CNS and shown that B cell depletion can worsen the symptoms of neurodegenerative diseases. We have demonstrated that exogenous B cells can be applied therapeutically to restore function in diverse injury models, including myocardial infarction, acute and chronic wound healing, 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%, and reduced gliosis 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. Moreover, our recent preliminary findings in the SOD1G93A mouse model of ALS showed that intravenous B cell administration significantly delays disease onset, extends survival, and is neuroprotective. In parallel, an independent group also reported a beneficial role of B cells in histopathological and functional outcome in a transient middle cerebral artery occlusion (MCAO) model in mice. Thus, our own data from four separate model systems, as well as independent findings in experimental ischemic stroke, indicate a robust and reproducible mechanism by which B cells respond to the molecular environment of injured tissues and support structural and functional repair. Collectively, these data support the scientific premise that B cell therapy will be beneficial for recovery after ICH. In this pilot proposal, we aim to show proof-of-concept to establish the potential of B cell immunomodulatory therapy for ICH, a novel application that has never before been reported. We plan to rigorously assess whether the neuroprotective benefits of direct B cell administration in the context of contusion TBI are reproducible in the context of a standardized ICH stroke model (Aim 1), and to determine whether the neuroprotective effect of B cell treatment can be induced through systemic, intravenous delivery (Aim 2). If successful, these data will form the basis for a more comprehensive proposal to further investigate the mechanisms of action and potential clinical applications of this promising therapeutic approach.

摘要：脑出血 (ICH) 约占中风的 15%，影响 200 万人全世界每年的死亡率在 5 年内高达 70%；不到 40% 的幸存者在 3 岁时独立生活几个月。 ICH 的治疗是支持性的，重点是逆转抗凝和限制血肿通过控制血压和充分止血来扩张。目前尚无特殊治疗方法可以改善 ICH 幸存者的神经系统结果，使得 ICH 的治疗成为一个未得到满足的关键需求。我们最近展示了一种基于 B 细胞的新型细胞免疫调节疗法加速组织生长的实用性和功效修复周围神经并防止中枢神经系统 (CNS) 损伤后的神经退行性影响。在除了产生抗体外，B 淋巴细胞通过直接调节免疫系统，也是免疫系统的有效调节者。细胞与细胞之间的相互作用以及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中的有益作用，并表明 B 细胞耗竭会恶化神经退行性疾病的症状。我们已经证明外源B细胞可以应用治疗上恢复多种损伤模型的功能，包括急性和慢性心肌梗塞伤口愈合和受控皮质撞击（CCI）创伤性脑损伤（TBI）。在我们的鼠标 CCI 模型中，单个受伤时向脑实质注射 B 细胞会显着降低学习和记忆能力损伤后 35 天，损伤体积减少 40-60%，神经胶质增生减少。初步研究表明 CCI 后 6 小时施用 B 细胞在减少运动学习缺陷方面仍然同样有效。此外，我们最近在 ALS 小鼠 SOD1G93A 模型中的初步发现表明，静脉注射 B 细胞给药可显着延迟疾病发作，延长生存期，并且具有神经保护作用。同时，一个独立小组还报告了 B 细胞在组织病理学和功能结果中的有益作用小鼠短暂性大脑中动脉闭塞（MCAO）模型。因此，我们自己的数据来自四个独立的模型系统以及实验性缺血性中风的独立发现表明，稳健且可重复的 B 细胞对受损组织的分子环境做出反应并支持结构和功能的机制功能修复。总的来说，这些数据支持了 B 细胞疗法将有益于以下科学前提： ICH 后恢复。在此试点提案中，我们的目标是展示概念验证，以确定 B 细胞的潜力 ICH 的免疫调节疗法，是一种以前从未报道过的新应用。我们计划严格评估直接 B 细胞给药在挫伤情况下是否具有神经保护作用 TBI 在标准化 ICH 卒中模型（目标 1）的背景下是可重复的，并确定是否 B 细胞治疗的神经保护作用可以通过全身静脉注射来诱导（目标 2）。如果如果成功的话，这些数据将成为进一步调查更全面提案的基础这种有前途的治疗方法的作用机制和潜在的临床应用。