The role of T-lymphocytes and antibodies in B-lymphocyte mediated post-stroke cognitive decline

T 淋巴细胞和抗体在 B 淋巴细胞介导的中风后认知衰退中的作用

• 批准号: 9752687
• 负责人: Jacob Zbesko
• 金额: $ 3.44万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2020-08-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752687
• 关键词: Adult; Animals; Antibodies; Antigens; Autoantibodies; Autoantigens; B-Lymphocytes; Behavioral; Blood Vessels; Brain; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cognitive; Cognitive deficits; Data; Delayed Memory; Dementia; Development; Diagnosis; Distal; Enzyme-Linked Immunosorbent Assay; Event; Excision; FDA approved; Flow Cytometry; Glial Fibrillary Acidic Protein; Helper-Inducer T-Lymphocyte; Hippocampus (Brain); Human; Hypoxia; Immunoassay; Impaired cognition; Individual; Infarction; Inflammation; Injections; Ischemic Stroke; Knock-out; Knockout Mice; Laboratories; Lead; Lesion; Long-Term Potentiation; Lymphocyte Activation; Measurement; Mediating; Memory impairment; Monoclonal Antibodies; Mus; Myelin Basic Proteins; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Neuraxis; Paper; Pathogenicity; Pharmaceutical Preparations; Plasma Cells; Prevalence; Production; Proteins; Proteolipids; Publishing; Reporting; Risk; Role; S100 Calcium Binding Protein; Serum; Spinal Cord; Stroke; Structure of germinal center of lymph node; Subcategory; Survivors; T-Lymphocyte; Techniques; Testing; Time; Toxicity Tests; Transgenic Mice; United States; Vascular Dementia; Work; adaptive immune response; behavior test; biomarker development; central nervous system injury; cognitive development; cost; disability; experience; mouse model; neurofilament; neurotoxicity; post stroke; post stroke cognitive impairment; post stroke dementia; prevent; protein B; response; stroke model; stroke patient; stroke survivor; therapy development

Abstract Stroke is one of the leading causes of adult disability in the United States, costing an estimated 33 billion dollars annually. Up to 30% of stroke patients experience cognitive decline in the first year after their stroke. There are no FDA approved drugs that can prevent post-stroke cognitive decline, a sub-category of vascular dementia, in part due to the mechanism(s) being poorly understood. Recently our lab published the first paper to show that an adaptive B-lymphocyte response to stroke can cause delayed cognitive dysfunction in mice, and that a similar adaptive immune response occurs in the brains of some human stroke patients that suffer from vascular dementia. This is the first evidence that in some people, post-stroke dementia may be caused by a B-lymphocyte response propagated by the stroke lesion. However, the precise mechanism by which B-lymphocytes mediate damage following stroke is still unknown. Discovering this mechanism is vital for developing treatments. Our proposed mechanism is that B-lymphocyte mediated cognitive impairment following stroke is T-cell dependent, requires a direct interaction between CD4+ T-follicular helper cells and B-lymphocytes, and is caused by the production of pathogenic central nervous system (CNS) specific autoantibodies. To test this hypothesis, I will generate transgenic mice with a conditional knockout of Bcl-6 in CD4+ cells. Bcl-6 is critical for the development of T-follicular helper cells, and so is critical for T-cell dependent B-lymphocyte activation. I will also inject into the brains of naïve animals, antibodies isolated from mice that have undergone a mouse model of stroke, and I will perform modified sandwich ELISAs to determine if mice generate the same six CNS specific autoantibodies that have been found to occur in human stroke patients. The completion of these aims will lead to a greater understanding of the mechanisms by which B-lymphocytes can contribute to the development of cognitive decline in the weeks and months after stroke, which is necessary for the development of treatments that target B-lymphocyte responses to stroke.

摘要 中风是美国成人残疾的主要原因之一， 330亿美元。高达30%的中风患者在第一次发病时会出现认知能力下降。 中风后一年。目前还没有FDA批准的药物可以预防中风后认知功能障碍 下降，血管性痴呆的一个子类别，部分原因是机制不佳 明白最近，我们的实验室发表了第一篇论文，表明适应性B淋巴细胞 对中风的反应可以导致小鼠延迟的认知功能障碍， 免疫反应发生在一些患有血管性中风的人类中风患者的大脑中， 痴呆这是第一个证据表明，在一些人，中风后痴呆症可能是由 由中风病灶传播的B淋巴细胞反应引起。然而，精确的机制 B淋巴细胞通过何种途径介导中风后的损伤仍然是未知的。发现这一 机制对于开发治疗方法至关重要。我们提出的机制是B淋巴细胞 中风后介导的认知障碍是T细胞依赖性的，需要直接相互作用， 在CD 4 + T-滤泡辅助细胞和B-淋巴细胞之间，是由产生 致病性中枢神经系统（CNS）特异性自身抗体。为了验证这个假设，我将 产生具有条件性敲除CD 4+细胞中Bcl-6的转基因小鼠。Bcl-6是一种重要的 T-滤泡辅助细胞的发育，因此对T细胞依赖的B-淋巴细胞至关重要 activation.我还将向幼稚动物的大脑中注射从老鼠身上分离出来的抗体， 我已经经历了一个中风的小鼠模型，我将进行修改的三明治ELISA， 确定小鼠是否产生相同的六种CNS特异性自身抗体， 发生在人类中风患者身上这些目标的完成将导致更大的 了解B淋巴细胞有助于发展的机制， 在中风后的几周和几个月内认知能力下降，这是发展所必需的。 针对中风的B淋巴细胞反应的治疗。

项目成果

Repeated Administration of 2-Hydroxypropyl-β-Cyclodextrin (HPβCD) Attenuates the Chronic Inflammatory Response to Experimental Stroke.

• DOI: 10.1523/jneurosci.0933-21.2021
• 发表时间: 2022-01-12
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Becktel DA;Zbesko JC;Frye JB;Chung AG;Hayes M;Calderon K;Grover JW;Li A;Garcia FG;Tavera-Garcia MA;Schnellmann RG;Wu HJ;Nguyen TV;Doyle KP
• 通讯作者: Doyle KP