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

摘要：脑出血约占卒中的15%，影响200万人。 全球每年死亡率高达70%，5年内死亡率高达70%；只有不到40%的幸存者在3年内独立生活 月份。脑出血的治疗是支持性的，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，还没有特效的治疗方法来改善 脑出血幸存者的神经学结果，使脑出血的治疗成为一个关键的未得到满足的需求。我们最近展示了 一种以B细胞为基础的新型细胞免疫调节疗法在加速组织中的应用和疗效 在中枢神经系统(CNS)损伤后进行外周修复并保护神经免受退行性影响。在……里面 除了产生抗体外，B淋巴细胞还是免疫系统的有效调节器，通过直接 细胞与细胞之间的相互作用以及通过分泌可溶性分子。最近的调查突显了 抗炎(调节)B细胞在中枢神经系统中的有益作用，并表明B细胞耗竭可以恶化 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 通过治疗恢复不同损伤模型的功能，包括急性和慢性心肌梗死 伤口愈合和受控皮质冲击(CCI)创伤性脑损伤(TBI)。在我们的鼠标CCI模型中， 损伤时向脑实质注射B细胞显著降低学习和记忆能力 损伤后35天，损伤体积减少40-60%，胶质细胞增生减少。初步研究表明 直到CCI后6h才给予B细胞，在减少运动学习障碍方面仍然同样有效。 此外，我们最近在ALS SOD1G93A小鼠模型上的初步发现表明，静脉注射B细胞 给药可显著延缓疾病的发作，延长生存期，并具有神经保护作用。同时，一个 独立研究小组还报告了B细胞在急性髓细胞白血病的组织病理学和功能预后中的有益作用。 小鼠短暂性大脑中动脉闭塞模型。因此，我们自己的数据来自四个独立的模型 系统，以及在实验性缺血性中风中的独立发现，表明了一种健壮和可重复的 B细胞对损伤组织的分子环境作出反应并支持结构和功能的机制 功能性修复。总的来说，这些数据支持了B细胞治疗将有益于 脑出血后恢复。在这个试点方案中，我们的目标是展示概念验证，以确定B细胞的潜力 免疫调节疗法治疗脑出血，这是一种以前从未报道过的新应用。我们计划 严格评估在挫伤情况下直接给予B细胞是否具有神经保护作用 在标准化的脑出血卒中模型(目标1)的背景下，脑损伤是可复制的，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，这些数据将成为更全面的提案的基础，以进一步调查 这一有前景的治疗方法的作用机制和潜在的临床应用。

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.