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: 8971965
• 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/8971965
• 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; multiple sclerosis patient; multiple sclerosis treatment; natalizumab; oligodendrocyte-myelin glycoprotein; peripheral blood; phase II trial; prevent; 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，可为包括感染在内的外蛋白提供免疫学保护。但是，越来越多地认识到，B细胞的免疫反应畸变也可能在人类炎症性疾病中起重要作用。一种这样的疾病是多发性硬化症（MS），这是人类中最常见的脑和脊髓炎症性疾病，这是成年人神经疾病的第二大最常见原因。最近的流行病学评估表明，每年在VA（http://www.va.gov/health/newsfeatures/20110309a.asp）中，每年有28,000多名多发性硬化症（MS）的退伍军人接受医疗服务。在全球范围内，有250万个MS的物理诊断患者。迄今为止，支持B细胞参与MS发病机理的作用的最佳证据也许来自MS中利妥昔单抗的临床试验。利妥昔单抗是一种药理学剂，可在血液和大脑中耗尽B淋巴细胞。这方面的数据由我的实验室发布，并在此赠款提案中显示。尽管有利于利妥昔单抗使MS患者有益，但有关该疾病中B细胞的许多问题仍未得到解决。重要的是，目前尚不清楚大脑和脊髓中是否需要B细胞为MS疾病伯恩（MS Disease Burnen）贡献，或者它们的作用是否仅限于中枢神经系统之外的器官。虽然B细胞可能会用利妥昔单抗耗尽，但在疾病后期，这些药物不太可能影响所有已经在大脑和SP绳索中的B细胞。其他研究人员和我们的小组的其他最新观察结果表明，MS中并非所有B细胞都会导致疾病。一些B细胞似乎正在减少疾病活性。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骨调节细胞。我的实验室最近产生了小鼠，其中B细胞无法迁移到大脑和脊髓中。否则这些动物是正常的。这些CD19.CRE+/ - »4-链接蛋白F/F小鼠的产生为我们提供了一个独特的机会，可以阐明B细胞在中枢神经系统外和其中的隔室中的作用。基于其他研究者的发表工作，我们现在还能够生成不同类型的B调节细胞和B非调节细胞。基于我们的初步结果，并使用我的实验室产生的试剂，我们将检验三个假设，该假设涉及B细胞子集在实验自身免疫性脑脊髓炎（EAE）MS的动物模型中的作用。我们假设，需要改善CNS自身免疫性疾病的早期阶段需要B调节细胞和脊髓之外的B代调节细胞。 b。我们假设B非调节细胞迁移到大脑和脊髓中对于永久性EAE临床疾病活性至关重要。理想情况下，一个相关的观察结果与患者发生的事件进行了观察结果。这可能会受到挑战，因为患者经常服用可能影响免疫学参数的不同形式的治疗，包括身体不同隔室中细胞的数量和类型。为了避免这些错误来源，我们将在II期跨国随机双盲临床试验中进行机械研究，该试验启动并由该赠款建议的PI领导。该赠款的所有临床和成像研究均由一个单独的实体资助，以及 不是此应用程序的主题。临床试验将评估已接受FDA批准药物Natalizumab治疗的患者。 Natalizumab可防止包括B细胞在内的细胞迁移到大脑和脊髓。所有患者的Natalizumab都将停止使用，并将启动另一种由FDA批准的疗法乙酸GLATIRAMER醋酸盐（GA），该疗法诱导B调节细胞。根据我们的初步动物和人类数据，c。我们假设由FDA批准的药物纳塔尔珠单抗阻止了B调节细胞和B非调节细胞的迁移。 d。我们假设由FDA批准的药物GA促进了MS患者外围的B调节细胞的产生，这有时会进入CNS。我们有信心，我们的研究将大大增加对B细胞子集作为疾病修饰剂的了解，并将其作为MS患者的潜在治疗剂。

项目成果

α4-integrin deficiency in B cells does not affect disease in a T-cell-mediated EAE disease model.

B 细胞中的α4-整合素缺乏不影响T 细胞介导的EAE 疾病模型中的疾病。

• DOI: 10.1212/nxi.0000000000000563
• 发表时间: 2019
• 期刊: Neurology(R) neuroimmunology & neuroinflammation
• 作者: Hussain,RehanaZ;Cravens,PetraD;Miller-Little,WilliamA;Doelger,Richard;Granados,Valerie;Herndon,Emily;Okuda,DarinT;Eagar,ToddN;Stüve,Olaf
• 通讯作者: Stüve,Olaf