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

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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.