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 淋巴细胞表面整合素阻断剂（即那他珠单抗 (α4)、维多珠单抗 (α4β7)）是 FDA 批准的一种药物 我们对其作用方式的理解是：治疗炎症性肠病（IBD）的策略。 然而，单剂量维多珠单抗对 B 细胞的影响并不完整且很少受到重视。 在健康志愿者中，会降低分泌性免疫球蛋白 (Ig)A (SIgA) 并削弱免疫反应 口服霍乱疫苗研究 β7 整合素在 B 细胞迁移、定位和功能中的作用。 IBD，我们与肿瘤坏死因子 (TNF) 过量产生的小鼠（TNFΔARE，会出现克罗恩病样回肠炎）进行杂交 和 IL10-/-（易患结肠炎）与 β7 缺陷（β7-/-）小鼠，意外的是，双突变（TNFΔARE/β7-/-）小鼠。 发展为加速回肠炎（发病较早且严重程度更严重），而 IL-10-/-β7-/- 发展为致命性结肠炎。 表型还可由抗 MAdCAM-1（α4β7-配体）抗体诱导。 表型并非由于缺乏视黄酸产生的αE(CD103)+树突状细胞、调节性T 然而，固有层明显减少。 (CD19+) B 细胞、IgA+ 浆细胞定位不良、管腔 IgA 缺乏以及微生物群差异 此外，来自 β7-/- 小鼠的粪便微生物群移植诱发了结肠炎。 IL-10 缺陷小鼠，表明 Ig 缺陷可能导致结肠炎病原体的传播性增殖。 因此，迫切需要了解整合素或其配体的持续阻断是否可能具有 我们发现β7缺陷小鼠的回肠炎和结肠炎的加速。 由受损的 B 细胞迁移和次优 IgA 转胞吞作用介导，导致肠道免疫球蛋白 为了检验这些假设，我们将检查： 1. B 细胞募集的作用。 和维持管腔 IgA 的存活率 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 整合素（即 αEβ7）与产生 IgA 的浆细胞对接的作用 上皮细胞和最佳 IgA 转胞吞作用这一研究具有重要意义，因为它开始解决 B 细胞的作用。 以及它们对 β7 整合素的独特关键依赖性，以回到肠道并最佳地转胞吞 IgA 维持体内平衡期间控制微生物群某些致病成分所需的 IgA 水平 和 IBD。了解淋巴细胞整合素在微生物群与其宿主之间界面的作用。 可能会导致更好地了解当前的抗整合素疗法如何发挥作用，甚至导致新的治疗方法 采取干预措施，防止对引发 IBD 的微生物群产生失调的免疫反应。