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淋巴细胞是白色血细胞，其提供针对外来蛋白的免疫保护，包括感染。然而，越来越多的人认识到，B细胞的免疫应答异常也可能在人类炎症性疾病中起重要作用。一种这样的病症是多发性硬化症（MS），其是人类大脑和脊髓的最常见的炎性病症，并且其是成人神经残疾的第二最常见原因。最近的流行病学评估表明，VA每年有超过28，000名患有多发性硬化症（MS）的退伍军人接受医疗护理（http：//www.va.gov/health/Newsdatures/20110309a.asp）。在世界范围内，有250万名医生诊断的MS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在MS中的临床试验。利妥昔单抗是一种消耗血液和大脑中的B淋巴细胞的药理学药剂。这方面的数据由我的实验室公布，并在本资助申请中显示。尽管认识到利妥昔单抗有益于MS患者，但关于这种疾病中的B细胞的许多问题仍然没有答案。重要的是，目前尚不清楚B细胞是否需要在大脑和脊髓中促成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B细胞可能被利妥昔单抗耗尽，但这些药物不太可能影响在疾病后期已经存在于脑和脊髓中的所有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中所有的B细胞都与疾病有关。某些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骨调节细胞。我的实验室最近培育出了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-integrin f/f小鼠的产生为我们提供了一个独特的机会，以澄清B细胞在中枢神经系统内外的作用。基于其他研究者发表的工作，我们现在也能够产生不同类型的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，我们将测试有关B细胞亚群在MS实验性自身免疫性脑脊髓炎（EAE）动物模型中作用的三个假设：a.我们假设在脑和脊髓外产生B调节细胞是改善早期CNS自身免疫性疾病所必需的; B.我们假设，B非调节细胞迁移到脑和脊髓中在EAE临床疾病活动的持续中是关键的;理想地，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学参数，包括身体不同隔室中细胞的数量和类型。为了规避这些错误来源，我们将在一项II期多国随机双盲临床试验期间进行机制研究，该试验由本资助申请的主要研究者负责启动。该补助金的所有临床和成像研究都由一个单独的实体资助， 不是本申请的主题。该临床试验将评估接受FDA批准的药物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）迁移到大脑和脊髓中。所有患者都将停用那他珠单抗，并开始接受另一种FDA批准的治疗，醋酸格拉替雷（GA），其诱导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批准的试剂那他珠单抗阻止B调节细胞和B非调节细胞迁移到CNS中; d.我们假设FDA批准的药剂GA促进MS患者外周中B调节细胞的产生，其最终将进入CNS。我们有信心，我们的研究将大大增加我们的知识B细胞亚群作为疾病修饰剂和潜在的治疗药物在MS患者。

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