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。项目摘要/摘要 淋巴细胞表面整合素的阻断（即纳他珠单抗（α4），vedolizumab（α4β7））是FDA批准的 治疗炎症性肠病（IBD）的策略。我们对他们的行动方式的理解是 它们对B细胞的影响不完整，几乎没有重点。但是，一剂Vedolizumab 在健康志愿者中 口服霍乱疫苗。解决β7整联蛋白在B细胞中迁移，定位和功能中的作用 IBD，我们跨越了肿瘤坏死因子（TNF） - 产生小鼠（TNFδARE，会发展Crohn的类似肠炎） 和IL10 - / - （易受colitic），带有β7-dific（β7 - / - ）小鼠。出乎意料的是，双突变体（tnfΔare/β7 - / - ）小鼠 发育的加速回肠炎（早期发作和严重程度较差），而IL-10 - / - β7 - / - 发生致命性结肠炎。这 表型可以另外由抗MADCAM-1（α4β7-LIGAND）抗体诱导。加速 表型不是由于视黄酸产生αe（CD103）+树突状细胞的缺乏，调节性T 细胞，调节性B细胞衍生的细胞因子或防御素。但是，有明显降低的固有层 （CD19+）B细胞，IgA+浆细胞的定位较差，腔内IgA缺乏以及微生物群的差异 共同兄弟姐妹的组成。此外，来自β7 - / - 小鼠的粪便菌群移植诱导结肠炎 IL-10缺陷小鼠，表明Ig缺陷可能允许散发性裂变。 那是迫切需要了解整合素或其配体是否持续阻断 对粘膜免疫的影响。我们假设β7缺乏小鼠的回肠炎和结肠炎的加速度 通过受损的B细胞迁移和次优的IgA转介症介导，导致肠道免疫球蛋白 病原体的赤字和扩散。要检验这些假设，我们将研究：1。B细胞募集的作用 和生存以维持腔IgA。 2。微生物群的变化如何改变课程和严重性 IBD？和3。进一步研究β7整合素（即αeβ7）在与IgA产生的浆细胞对接的作用 上皮和最佳IGA转介症。这项投资很重要，因为它开始解决B细胞的作用 以及它们对β7整合素对肠道的独特临界依赖性，并最佳地跨环蛋白IgA到 保持所需的IgA水平，以控制稳态期间微生物群的某些病原元件 和IBD。了解淋巴细胞整合蛋白在微生物群与其宿主之间的界面中的作用 可能会更好地了解当前的抗整合素治疗，甚至导致新的疗法 干预措施，以防止对触发IBD的微生物群体失调的免疫响应。