B cell-mediated immune regulation

B细胞介导的免疫调节

• 批准号: 9548004
• 负责人: Bonnie N Dittel
• 金额: $ 45.15万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9548004
• 关键词: Address; Alpha Cell; Animals; Antibodies; Attenuated; Autoantigens; Autoimmune Responses; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; CCL22 gene; CCR5 gene; Cell Count; Cell surface; Cells; Cessation of life; Characteristics; Chronic Disease; Clinical; Data; Development; Disease; Disease model; Exhibits; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Flow Cytometry; Germ Lines; Goals; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IgG1; Immunoglobulin D; Immunoglobulin M; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Investigation; Kinetics; MS4A1 gene; Maintenance; Mediating; Migration Assay; Multiple Sclerosis; Mus; PTPRC gene; Patients; Phenotype; Play; Population; Production; Recovery; Refractory; Regulatory T-Lymphocyte; Relapsing-Remitting Multiple Sclerosis; Role; Series; Severities; Severity of illness; Signal Transduction; Spleen; T-Lymphocyte; Testing; Therapeutic; Tissues; Transgenic Organisms; Translations; attenuation; base; chemokine; clinically relevant; immunoregulation; migration; mouse model; multiple sclerosis treatment; novel; overexpression; peripheral blood; rituximab; study characteristics; therapeutic evaluation; transcriptome sequencing

Inflammation that accompanies chronic disease, if uncontrolled, leads to severe tissue damage resulting in debilitation and even death. It is well established that CD4+Foxp3+ T regulatory cells (Treg) play an essential role in the suppression of autoimmune and inflammatory responses. In addition to Treg, B cells have also emerged as an important attenuator of inflammation in a variety of diseases, including autoimmunity and hypersensitivities. We were the first to show that B cells attenuate disease severity in autoimmunity using the mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Shortly thereafter the concept of regulatory B cells or Breg emerged. Even though B cells have been shown to regulate inflammation via IL-10 production, they cannot be identified by a definitive cell surface phenotype. In contrast, in our studies investigating IL-10-independent Breg mechanisms, we have successfully identified a cell surface phenotype that we have used to track and purify Breg. Of significance to the translation of our findings is that human Breg promote Treg proliferation. This is the first example of a definitive cell surface phenotype that can be used to identify and purify a specific population of Breg in both mouse and humans. To emphasize their unique function, we termed them B Treg helper cells (BTrh). The goal of this application is to gain a better understanding of the development and function of BTrh and will test the hypothesis that BTrh via their induction of Treg proliferation will have clinical relevance in the attenuation of inflammatory diseases. This hypothesis will be tested in two specific aims: Aim 1. Gain a better understanding of unique BTrh characteristics by studying their developmental status, functional requirements and localization with Treg and Aim 2. Determine the therapeutic potential of GITRL+ BTrh and to test the hypothesis that efficacy of B cell depletion by rituximab in MS is due to its inability to deplete BTrh. Together, the proposed studies represent a tightly focused coordinated series of investigations aimed at broadening the importance of BTrh in a number of clinically important inflammatory disorders in humans.

伴随慢性疾病的炎症，如果不受控制，会导致严重的组织损伤，导致 衰弱甚至死亡。众所周知，CD4+ FOXP3+ T调节细胞（TREG）的作用是必不可少的 在抑制自身免疫和炎症反应中的作用。除了Treg，B细胞还 成为各种疾病中炎症的重要衰减，包括自身免疫和 超敏反应。我们是第一个证明B细胞使用该B细胞减轻自身免疫性疾病严重程度的人 多发性硬化症的小鼠模型（MS），实验自身免疫性脑脊髓炎（EAE）。不久 此后，出现了调节B细胞或Breg的概念。即使已经证明了B细胞 通过IL-10产生调节炎症，无法通过确定的细胞表面表型来识别它们。在 在研究IL-10独立的布雷格机制的研究中，我们成功地确定了 我们用来跟踪和净化Breg的细胞表面表型。对我们的翻译具有重要意义 发现是人类的布雷格促进了Treg的增殖。这是确定细胞表面的第一个例子 可以用来识别和净化小鼠和人类中特定布雷格的特定人群的表型。到 强调它们的独特功能，我们称它们为B Treg Helper细胞（BTRH）。该应用的目的是 更好地了解BTRH的发展和功能，并将检验BTRH通过 他们诱导Treg增殖将在炎症性疾病的衰减中具有临床相关性。 该假设将以两个具体的目的进行检验：目标1。对独特的BTRH有更好的了解 通过研究其发展状况，功能要求和与Treg和Treg的本地化的特征 AIM 2。确定GITRL+ BTRH的治疗潜力，并检验B细胞功效的假设 利妥昔单抗在MS中耗尽的是由于其无法消耗BTRH。共同提出的研究代表 紧密集中的一系列调查旨在扩大BTRH的重要性 人类临床上重要的炎症性疾病。