Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease

天然抗体和 B1 细胞在纤维增生性肺病中的作用

• 批准号: 10752129
• 负责人: Riley T Hannan
• 金额: $ 7.06万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752129
• 关键词: Adoptive Transfer; Alveolar; Animal Model; Animals; Antibody-Producing Cells; Appearance; B-Lymphocytes; Biological Assay; Bleomycin; CCL20 gene; CCR6 gene; Cell Compartmentation; Cell Culture Techniques; Cells; Chemotaxis; Chronic; Cicatrix; Circulation; Data; Development; Diagnosis; Disease; Disease Progression; Environment; Fibrosis; Frequencies; Goals; Human; Immune; Immunity; Immunoglobulin M; Immunoglobulins; Immunology; In Vitro; Inflammatory; Injury; Interstitial Lung Diseases; Intervention; Invaded; Label; Ligands; Lung; Lung diseases; Lymphatic Endothelium; Lymphocyte; Lymphoid; Measures; Mediating; Mesothelium; Modeling; Mus; Myelogenous; Myofibroblast; Natural Immunity; Pathologic; Pathology; Pleura; Pleural; Pleural cavity; Population; Process; Production; Progressive Disease; Pulmonary Fibrosis; Research; Role; Science; Series; Severities; Signal Pathway; Signal Transduction; Sterility; Stromal Cells; T-Lymphocyte; Testing; Tissues; Training; Transgenic Mice; Universities; Vascular Endothelium; Virginia; Work; beta-Chemokines; career; career development; chemokine receptor; experimental study; fibrotic lung; idiopathic pulmonary fibrosis; in vivo; in vivo imaging; lung injury; lymphatic circulation; monolayer; mouse model; natural antibodies; novel; oxidized lipid; pharmacologic; receptor expression; recruit; response; skills; spatial relationship; tertiary lymphoid organ; tissue repair; tool; trafficking; treatment arm

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) of progressive scarring and no cure. Current pharmacologic interventions in IPF target canonical myofibroblast signaling, but at best slow disease progression, and median survival post diagnosis is 3-5 years. Dysregulated immunity of myeloid and lymphoid populations is party to the progression of fibrotic disease. Lung B cell frequency increases in human ILDs, and in both sterile and infectious animal models of fibroproliferative lung injury. The appearance of B cells in the alveolar spaces, a phenomena absent in healthy tissue, is characterized by both single lymphocytes and in larger, organized accumulations of lymphocytes termed tertiary lymphoid organs (TLOs). Our preliminary data show natural B cell immunity is protective in lung injury. Natural immunity is mediated B-1 cells, a type of T-cell independent B cell which produces natural antibodies (nAb). These nAb are largely IgM, and are protective in inflammatory and fibrotic pathologies. B-1 cells primarily reside in the serosal cavities, including millions of B-1 cells in close contact with the lung in the pleural cavity. We believe these pleural B-1 cells are a reservoir of nAb producing cells which are highly responsive to changes in soluble factor signaling from the lung. In supporting data for this proposal, we have found that increases in a B-1 secreted species of nAb against oxidized lipid is protective against bleomycin-induced lung injury in mice. The increase in lung B-1 cells and nAb after lung injury occurs concomitant with changes in chemokine receptor (CR) expression in the pleural B- 1 cell compartment. Our central hypothesis is that pleural B-1 cells traffic to the lung in a CR-dependent manner and protect from fibroproliferative injury via production of nAb. Our overarching goal is to understand the pleural B-1 cell response to lung injury, and elucidate the mechanisms by which nAb is protective in disease. To this end, we propose to test following aims: First, test the hypothesis that pleural B-1 cells traffic to the lung during lung injury in a CR-dependent manner. Second, test the hypothesis that secretion of nAb by B-1 cells is protective in fibrotic lung injury. These experiments will make use of extant transgenic mouse lines and established mechanistic approaches both in vivo and in vitro to dissect the B cell-Fibrosis axis in lung injury. It is novel in that it will answer mechanistic questions relating natural immunity in fibrosis, and identify new and potentially targetable signaling pathways in fibroproliferative disease – vital for the development of better treatments. The environment in which I will perform the proposed work could not be better suited; the University of Virginia is a world-class research university and we have assembled a world- class team to support this endeavor through intentional planning for both science and personal/professional development.

项目摘要 特发性肺纤维化（IPF）是进行性疤痕和无法治愈的间质性肺疾病（ILD）。 IPF靶标构成肌纤维细胞信号传导的当前药物化学干预措施，但最多缓慢疾病 诊断后的进展和中位生存期为3 - 5年。髓样和淋巴机的免疫失调 种群是纤维化疾病进展的政党。人ILD的肺B细胞频率增加，并且 在纤维增生性肺损伤的无菌和感染性动物模型中。 B细胞在 牙槽空间是健康组织中缺乏的现象，其特征是单个淋巴细胞和 淋巴细胞的较大，有组织的积累称为第三纪淋巴机构（TLOS）。我们的初步数据 表明天然B细胞免疫性受到肺损伤的保护。天然免疫力是介导的B-1细胞，一种T细胞 产生天然抗体（NAB）的独立B细胞。这些NAB在很大程度上是IgM，并且受到保护 炎症和纤维化病理。 B-1细胞主要驻留在血清腔中，包括数百万B-1 细胞与胸膜腔中的肺部紧密接触。我们相信这些胸膜B-1单元是 NAB产生的细胞对肺部固体因子信号的变化高度响应。 在支持该提案的数据时，我们发现B-1分泌的NAB物种增加了 氧化脂质受到小鼠博来霉素诱导的肺损伤的保护。肺B-1细胞的增加和 肺损伤后的NAB随着胸膜B-中趋化因子受体（CR）表达的变化而发生的NAB 1个细胞室。 我们的中心假设是胸膜B-1细胞以CR依赖性方式传播到肺部，并且 通过生产NAB来防止纤维增生性损伤。我们的总体目标是了解 胸膜B-1细胞对肺损伤的反应，并阐明了NAB在疾病中受到保护的机制。 为此，我们建议测试以下目的：首先，测试胸膜B-1细胞流向肺的假设 在肺损伤期间以CR依赖性方式。其次，检验以下假设，即B-1细胞分泌NAB是 纤维化肺损伤的保护性。这些实验将利用扩展的转基因小鼠系和 建立的机械方法在体内和体外都可以在肺损伤中剖析B细胞纤维化轴。它 是新颖的，因为它将回答与纤维化中自然免疫有关的机理问题，并确定 纤维增生性疾病中的新的且潜在的目标信号通路 - 对于 发展更好的治疗方法。我将执行拟议工作的环境不可能是 更适合；弗吉尼亚大学是一所世界一流的研究大学，我们已经聚集了一个世界 - 班级团队通过对科学和个人/专业的有意计划来支持这项努力 发展。