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

• 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
• 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' 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

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200万人中风的15% 5年内死亡率高达70%;不到40%的幸存者在3岁时独立工作 个月ICH的治疗是支持性的，重点是逆转抗凝和限制血肿 通过血压控制和充分止血进行扩张。目前，没有具体的治疗方法可以改善 ICH幸存者的神经系统结局，使ICH治疗成为一个关键的未满足需求。我们最近的研究表明 基于B细胞的新型细胞免疫调节疗法的效用和功效， 在中枢神经系统（CNS）损伤后，在外周进行修复并保护免受神经退行性影响。在 除了产生抗体外，B淋巴细胞是免疫系统的有效调节者， 细胞-细胞相互作用和通过分泌可溶性分子。最近的调查强调， 抗炎（调节）B细胞在CNS中的有益作用，并显示B细胞耗竭可使 神经退行性疾病的症状我们已经证明，外源性B细胞可以应用于 在治疗上恢复各种损伤模型的功能，包括心肌梗死、急性和慢性 伤口愈合和可控皮质撞击（CCI）创伤性脑损伤（TBI）。在小鼠CCI模型中， 在损伤时向脑实质注射B细胞显著降低了学习和记忆能力 在损伤后35天，损伤体积减少40- 60%，并且神经胶质增生减少。初步研究表明 在CCI后6小时给予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SOD 1G 93 A小鼠ALS模型中的初步发现表明，静脉内B细胞 给药显著延迟疾病发作，延长存活，并且具有神经保护作用。与此同时， 一个独立的研究小组也报道了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，表明一个强大的和可重复的 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细胞疗法将有利于 ICH后恢复。在这个试点提案中，我们的目标是展示概念验证，以确定B细胞的潜力 ICH的免疫调节治疗，这是一种以前从未报道过的新应用。我们计划 严格评估在挫伤的情况下直接给予B细胞的神经保护益处 TBI在标准化ICH卒中模型的背景下是可重现的（目标1），并确定TBI是否 B细胞处理的神经保护作用可以通过全身静脉内递送来诱导（目的2）。如果 如果成功，这些数据将构成一个更全面的建议的基础，以进一步调查 这种有前途的治疗方法的作用机制和潜在的临床应用。