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.

项目总结 特发性肺纤维化(IPF)是一种进行性瘢痕形成且无法治愈的间质性肺疾病(ILD)。 目前IPF的药物干预针对的是规范的肌成纤维细胞信号，但充其量只能减缓疾病的发展 进展，确诊后中位生存期为3-5年。髓系和淋巴系免疫失调 人口是纤维化疾病进展的一部分。人类ILDS患者肺B细胞频率增加，并且 在纤维增生性肺损伤的无菌和感染动物模型中。B细胞在卵巢癌中的出现 肺泡腔是一种在健康组织中不存在的现象，其特征是单个淋巴细胞和 较大的、有组织的淋巴细胞聚集，称为第三淋巴器官(TLO)。我们的初步数据 表明自然B细胞免疫在肺损伤中具有保护性作用。自然免疫是由T细胞的一种--B-1细胞介导的 产生天然抗体(NAB)的独立B细胞。这些NAB主要是IgM，对人体有保护作用 炎性和纤维化病理。B-1细胞主要驻留在浆膜腔内，包括数百万的B-1 胸膜腔内与肺密切接触的细胞。我们认为这些胸膜B-1细胞是 NAB产生细胞，对来自肺的可溶性因子信号的变化高度反应。 在支持这项提议的数据中，我们发现B-1分泌的NAB物种的增加对 氧化脂质对博莱霉素所致小鼠肺损伤有保护作用。肺B-1细胞和 肺损伤后NAB伴随着胸膜趋化因子受体(CR)表达的变化。 1个细胞隔室。 我们的中心假设是胸膜B-1细胞以CR依赖的方式进入肺并且 通过产生NAB保护纤维增生性损伤。我们的首要目标是了解 胸膜B-1细胞对肺损伤的反应，并阐明NAB在疾病中起保护作用的机制。 为此，我们建议检验以下目标：首先，检验胸膜B-1细胞进入肺部的假设 在肺损伤期间，以CR依赖的方式。第二，检验B-1细胞分泌NAB的假设 对纤维化肺损伤的保护作用。这些实验将利用现有的转基因小鼠品系和 建立了在体内和体外解剖肺损伤中B细胞-纤维化轴的机制方法。它 是新颖的，因为它将回答与纤维化中的自然免疫有关的机械性问题，并确定 纤维增生性疾病中新的和潜在的靶向信号通路-对 开发更好的治疗方法。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级的研究型大学，我们聚集了一个世界- 班级团队通过科学和个人/专业的有目的的计划来支持这一努力 发展。