Determining the compartmental role of B cell subsets during CNS autoimmunity

确定 B 细胞亚群在 CNS 自身免疫过程中的区室作用

• 批准号: 8660224
• 负责人: OLAF STUVE
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660224
• 关键词: Adult; Affect; Algorithms; Animal Model; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Applications Grants; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biological Assay; Blood; Brain; Brain Diseases; CD19 gene; CNS autoimmune disease; CNS autoimmunity; Caring; Cell Count; Cells; Cerebrospinal Fluid; Clinical; Clinical Trials; Complement; Data; Diagnosis; Disease; Double-Blind Method; Epidemiology; Error Sources; Event; Experimental Autoimmune Encephalomyelitis; FDA approved; Flow Cytometry; Funding; Generations; Grant; Head; Health; Human; Image; In Vitro; Infection; Inflammatory; Integrins; Interferon beta-1a; Knowledge; Laboratories; Leukocytes; Lymphoid; MS4A1 gene; Magnetic Resonance Imaging; Medical; Methods; Modeling; Monoclonal Antibodies; Monoclonal Antibody CD20; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neurologic; Organ; Pathogenesis; Patients; Peripheral; Phase; Phase II Clinical Trials; Physicians; Plasma Cells; Play; Prevalence; Proteins; Publishing; Randomized; Reagent; Recombinants; Relapse; Research Personnel; Role; Specificity; Spinal Cord; Staging; T-Lymphocyte; Testing; Therapeutic Agents; Time; Veterans; Work; animal data; arm; base; burden of illness; cell type; cohort; copolymer; copolymer 1; disability; human data; in vitro testing; in vivo; migration; natalizumab; oligodendrocyte-myelin glycoprotein; peripheral blood; prevent; public health relevance; response; rituximab; week trial

DESCRIPTION (provided by applicant): B lymphocytes are white blood cells that provide immunological protection against foreign proteins, including infections. However, it is increasingly being recognized that an aberration in immunological responses by B cells may also play an important role in human inflammatory disorders. One such disorder is multiple sclerosis (MS), which is the most common inflammatory disorder of the brain and spinal cord in humans, and which is the second most common cause of neurological disability in adults. Recent epidemiological assessments suggest that over 28,000 Veterans with multiple sclerosis (MS) receive medical care annually in VA (http://www.va.gov/health/NewsFeatures/20110309a.asp). World-wide, there are 2.5 million physician-diagnosed patients with MS. Perhaps the best evidence to date that support a role for B-cell involvement in MS pathogenesis come from clinical trials with rituximab in MS. Rituximab is a pharmacological agent that depletes B lymphocytes in the blood and the brain. Data in this regard was published by my laboratory and is shown in this grant proposal. Despite the recognition that rituximab benefits patients with MS, many questions regarding B cells in this disorder have remained unanswered. Importantly, it is currently unclear whether B cells are required in the brain and spinal cord to contribute to MS disease burden, or whether their role is limited to organs outside the central nervous system. While B cells may be depleted by rituximab, it is unlikely that these agents affect all B cells that are already in the brain and spnal cord during later stages of the disease. Other recent observations by other investigators and our group suggest that not all B cells in MS are contributing to disease. Some B cells appear to be diminishing disease activity. We refer to these B cells as B regulatory cells, and to all other B cells as B bon-regulatory cells. My laboratory recent has recently generated mice in which B cells cannot migrate into the brain and spinal cord. These animals are otherwise developmentally normal. The generation of these CD19.Cre+/--¿4-integrinf/f mice provides us a unique opportunity to clarify the role of B cells in compartments outside of the central nervous system and within it. Based on the published work by other investigators, we are also now able to generate different kinds of B regulatory cells and B non-regulatory cells. Based on our preliminary results, and using the reagents my laboratory has generated, we will test three hypothesis regarding the role of B cell subsets in the experimental autoimmune encephalomyelitis (EAE) animal model of MS: a. we hypothesize that the generation of B regulatory cells outside of the brain and spinal cord is required for amelioration of early stages of CNS autoimmune disease; b. we hypothesize that migration of B non-regulatory cells into the brain and spinal cord is critical in perpetuating EAE clinical disease activity; Ideally, one correlates observations made in an animal model with events that occur in patients. This can be challenging, as patients often take different forms of treatment that can affect immunological parameters, including the number and type of cells in different compartments of the body. To circumvent these sources of error, we will conduct mechanistic studies during a phase II multi-national randomized double-blind clinical trial that was initiated and is headed by the PI of this grant proposal. All clinical and imaging studies of this grant are funded by a separate entity, and are not subject of this application. The clinical trial will assess patients who have been treated with the FDA-approved agent natalizumab. Natalizumab prevents cells, including B cells, from migrating into the brain and spinal cord. Natalizumab will be discontinued in all patients, and they will be started on another FDA-approved therapy, glatiramer acetate (GA), which induces B regulatory cells. Based on our preliminary animal and human data, c. we hypothesize that the FDA-approved agent natalizumab prevents the migration of B regulatory cells and B non-regulatory cells into the CNS; d. we hypothesize that the FDA-approved agent GA promotes the generation of B regulatory cells in the periphery of patients with MS, which eventually will gain access to the CNS. We are confident that our studies will substantially increase our knowledge of B cell subsets as disease modifiers and as potential therapeutic agents in patients with MS.

描述（由申请人提供）： B 淋巴细胞是白细胞，可提供针对外来蛋白质（包括感染）的免疫保护。然而，人们越来越认识到 B 细胞免疫反应的异常也可能在人类炎症性疾病中发挥重要作用。其中一种疾病是多发性硬化症（MS），它是人类大脑和脊髓最常见的炎症性疾病，也是成人神经功能障碍的第二大常见原因。最近的流行病学评估表明，每年有超过 28,000 名患有多发性硬化症 (MS) 的退伍军人在 VA 接受医疗护理 (http://www.va.gov/health/NewsFeatures/20110309a.asp)。全球有 250 万医生诊断患有多发性硬化症的患者。也许迄今为止支持 B 细胞参与 MS 发病机制的最佳证据来自利妥昔单抗治疗 MS 的临床试验。利妥昔单抗是一种消耗血液和大脑中 B 淋巴细胞的药物。这方面的数据由我的实验室发布，并显示在本拨款提案中。尽管人们认识到利妥昔单抗对 MS 患者有益，但有关这种疾病中 B 细胞的许多问题仍未得到解答。重要的是，目前尚不清楚大脑和脊髓是否需要 B 细胞来增加 MS 疾病负担，或者它们的作用是否仅限于中枢神经系统以外的器官。虽然利妥昔单抗可能会耗尽 B 细胞，但这些药物不太可能在疾病后期影响大脑和脊髓中已有的所有 B 细胞。其他研究人员和我们小组最近的其他观察结果表明，并非 MS 中的所有 B 细胞都会导致疾病。一些 B 细胞似乎正在减少疾病活动。我们将这些 B 细胞称为 B 调节细胞，将所有其他 B 细胞称为 B bon 调节细胞。我的实验室最近培育了 B 细胞无法迁移到大脑和脊髓的小鼠。这些动物在其他方面发育正常。 这些 CD19.Cre+/--¿4-integrinf/f 小鼠的产生为我们提供了一个独特的机会来阐明 B 细胞在中枢神经系统外部和内部的隔室中的作用。根据其他研究人员发表的工作，我们现在还能够生成不同种类的 B 调节细胞和 B 非调节细胞。根据我们的初步结果，并使用我实验室生产的试剂，我们将测试关于 B 细胞亚群在 MS 实验性自身免疫性脑脊髓炎 (EAE) 动物模型中的作用的三个假设：我们假设，在大脑和脊髓外产生 B 调节细胞是改善中枢神经系统自身免疫性疾病早期阶段所必需的； b.我们假设 B 非调节细胞迁移到大脑和脊髓对于 EAE 临床疾病活动的持续至关重要；理想情况下，将动物模型中的观察结果与患者中发生的事件相关联。这可能具有挑战性，因为患者经常采取不同形式的治疗，这些治疗可能会影响免疫参数，包括身体不同部位的细胞数量和类型。为了避免这些错误来源，我们将在一项由本拨款提案的 PI 发起并领导的 II 期跨国随机双盲临床试验中进行机制研究。这笔拨款的所有临床和影像研究均由一个单独的实体资助，并且 不是本申请的主题。该临床试验将评估接受 FDA 批准的那他珠单抗治疗的患者。那他珠单抗可防止细胞（包括 B 细胞）迁移到大脑和脊髓。所有患者将停止使用那他珠单抗，他们将开始接受 FDA 批准的另一种疗法，即醋酸格拉替雷 (GA)，该疗法可诱导 B 调节细胞。根据我们初步的动物和人类数据，c。我们假设 FDA 批准的药物那他珠单抗可阻止 B 调节性细胞和 B 非调节性细胞迁移至 CNS； d.我们假设 FDA 批准的药物 GA 促进 MS 患者外周 B 调节细胞的生成，最终进入中枢神经系统。我们相信，我们的研究将大大增加我们对 B 细胞亚群作为疾病调节剂和多发性硬化症患者潜在治疗药物的认识。