Control by Beta 7 integrins of the bacterial triggers of IBD

Beta 7 整合素控制 IBD 细菌触发因素

• 批准号: 10481726
• 负责人: Jesus Rivera-Nieves
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10481726
• 关键词: Acceleration; Address; Affect; Antibodies; B-Lymphocytes; Bacteria; Bacterial Antigens; CD19 gene; Cell physiology; Cells; Cholera Vaccine; Chronic; Circulation; Clinical; Colitis; Crohn' s disease; Cytometry; Data; Defense Mechanisms; Defensins; Dendritic Cells; Dependence; Disease Progression; Disease model; Docking; Dose; Elements; Epithelium; Exhibits; FDA approved; Feces; Financial Hardship; Growth; Healthcare Systems; Home; Homeostasis; Homing; Human; IgA Deficiency; Ileitis; Immune Tolerance; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunologist; Immunology; Impairment; Individual; Inflammatory Bowel Diseases; Integrins; Interleukin-10; Intervention; Intestines; Investigation; Lamina Propria; Lead; Ligands; Lymphocyte; Maintenance; Mediating; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mus; Mutant Strains Mice; Oral; Pathogenicity; Patients; Peer Review; Pharmaceutical Preparations; Phenotype; Plasma Cells; Play; Predisposition; Process; Production; Proliferating; Publishing; Regulation; Regulatory T-Lymphocyte; Reporting; Ribosomal RNA; Role; Secretory Immunoglobulin A; Severities; Siblings; Surface; T-Lymphocyte; TNF gene; Testing; Therapeutic; Tissues; Translating; Tretinoin; United States; Veterans; Work; YY1 Transcription Factor; cell motility; cellular targeting; cytokine; drug action; dysbiosis; early onset; experience; fecal transplantation; gut microbiota; healthy volunteer; microbiota; migration; mouse model; mucosal addressin cell adhesion molecule-1; mutant; natalizumab; novel; pathobiont; prevent; receptor; recruit; response; transcytosis; treatment strategy

7. Project Summary/Abstract The blockade of lymphocyte surface integrins (i.e. natalizumab (α4), vedolizumab (α4β7)) is an FDA-approved strategy for the treatment of inflammatory bowel disease (IBD). Our understanding of their mode of action is incomplete and little emphasis has been placed on their effect on B cells. However, a single dose of vedolizumab in healthy volunteers lowers secretory immunoglobulin (Ig)A (SIgA) and weakens the immunization response to oral cholera vaccine. To address the role of β7 integrins for the migration, localization and function of B cells in IBD, we crossed tumor necrosis factor (TNF)-overproducing mice (TNFΔARE, which develop Crohn’s-like ileitis) and IL10-/- (colitic-prone) with β7-deficient (β7-/-) mice. Unexpectedly, double mutant (TNFΔARE/β7-/-) mice developed accelerated ileitis (earlier onset and worse severity), whereas IL-10-/-β7-/- develop lethal colitis. This phenotype could additionally be induced by an anti-MAdCAM-1(α4β7-ligand) antibody. The accelerated phenotypes were not due to a deficiency of retinoic acid-producing αE(CD103)+ dendritic cells, regulatory T cells, regulatory B cell-derived cytokines or defensins. There was, however, markedly decreased lamina propria (CD19+) B cells, poor localization of IgA+ plasma cells, luminal IgA deficiency, and differences in microbiota composition in co-housed siblings. Furthermore, fecal microbiota transplants from β7-/- mice induced colitis in IL-10-deficient mice, suggesting that an Ig deficit may allow transmissible proliferation of colitogenic pathobionts. Thus, there is a critical need to understand whether sustained blockade of integrins or their ligands may have implications for mucosal immunity. We hypothesize that the acceleration of ileitis and colitis in β7-deficient mice is mediated by impaired B cell migration and suboptimal IgA transcytosis leading to an intestinal immunoglobulin deficit and proliferation of pathobionts. To test these hypotheses, we will examine: 1. the role of B cell recruitment and survival to maintain luminal IgA. 2. How do changes in microbiota composition alter the course and severity of IBD? and 3. Further examine the role of β7 integrin (i.e., αEβ7) for docking of IgA-producing plasma cells with epithelium and optimal IgA transcytosis. This investigation is significant as it begins to address the role of B cells and their unique critical dependence on β7 integrins to home to the intestine and optimally transcytose IgA to maintain the required IgA levels that control certain pathogenic elements of the microbiota during homeostasis and IBD. Understanding the role of lymphocyte integrins at the interface between the microbiota and its host may lead to a better understanding of how do current anti-integrin therapeutics work and even lead to new interventions to prevent initiation of the dysregulated immune response to the microbiota that triggers IBD.

7.项目总结/摘要 淋巴细胞表面整联蛋白（即那他珠单抗（α4）、Vedolizumab（α4β7））的阻断是FDA批准的一种 治疗炎症性肠病（IBD）的策略。我们对他们行动方式的理解是 它们对B细胞的作用是不完整的，也很少受到重视。然而，Vedolizumab单次给药 在健康志愿者中，降低分泌型免疫球蛋白（IG）A（SIgA）并减弱对 口服霍乱疫苗为了阐明β7整合素在B细胞迁移、定位和功能中的作用， IBD时，我们将肿瘤坏死因子（TNF）过度产生的小鼠（TNFΔARE，发生克罗恩样回肠炎） 和IL 10-/-（结肠炎倾向）与β7-缺陷（β7-/-）小鼠。出乎意料的是，双突变（TNFΔARE/β7-/-）小鼠 发生加速性回肠炎（发病较早且严重程度更差），而IL-10-/-β7-/-发生致死性结肠炎。这 表型可另外由抗MAdCAM-1（α4β7-配体）抗体诱导。加速 表型不是由于产生视黄酸的αE（CD 103）+树突状细胞、调节性T细胞和细胞因子的缺乏所致。 细胞、调节性B细胞衍生的细胞因子或防御素。然而，固有层明显减少， (CD19+）B细胞、伊加+浆细胞定位不良、管腔伊加缺乏和微生物群差异 在共同居住的兄弟姐妹组成。此外，来自β7-/-小鼠的粪便微生物群移植物在小鼠中诱导结肠炎。 IL-10缺陷的小鼠，表明IG缺陷可能允许大肠杆菌致病菌的可传播增殖。 因此，迫切需要了解持续阻断整联蛋白或其配体是否可能具有以下作用： 对粘膜免疫的影响。我们假设β7缺乏小鼠回肠炎和结肠炎的加速 由受损的B细胞迁移和次优的伊加转胞吞作用介导，导致肠免疫球蛋白 致病菌的缺陷和增殖。为了验证这些假设，我们将研究：1。B细胞募集作用 维持管腔伊加。2.微生物群组成的变化如何改变病程和严重程度 IBD？和3.进一步检查β7整联蛋白的作用（即，αEβ7）用于产生IgA的浆细胞与 上皮和最佳伊加转胞吞作用。这项研究是重要的，因为它开始解决B细胞的作用 以及它们对β7整联蛋白的独特关键依赖性，以归巢到肠道，并最佳地转胞质糖伊加， 维持在体内平衡期间控制微生物群的某些致病元素所需的伊加水平 IBD。了解淋巴细胞整合素在微生物群及其宿主之间界面的作用 可能会导致更好地了解目前的抗整联蛋白治疗如何工作，甚至导致新的 干预措施，以防止引发IBD的微生物群的免疫反应失调。