Role of Complement-Driven Pulmonary Vascular Inflammation in PH

补体驱动的肺血管炎症在 PH 中的作用

• 批准号: 10686932
• 负责人: Brian Barkley Graham
• 金额: $ 48.86万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686932
• 关键词: Affect; Alternative Complement Pathway; Anaphylatoxins; Antigens; Autoimmune; Automobile Driving; Blood Platelets; Blood Vessels; C3AR1 gene; CD4 Positive T Lymphocytes; Cells; Cessation of life; Clinical; Complement; Complement Activation; Complement component C1; Complex; Country; Development; Disease; Elements; Etiology; Exposure to; Extracellular Matrix; Face; Fresh Water; Goals; Heterogeneity; Human; Hypoxia; Immune; Immune system; Immunosuppression; Infection; Inflammation; Innate Immune Response; Lectin; Leukocytes; Link; Lung; Macrophage; Mediating; Mus; Natural Immunity; Parasites; Pathogenesis; Pathology; Patients; Persons; Phenotype; Plasma; Pre-Clinical Model; Pulmonary Hypertension; Recovery; Regulatory T-Lymphocyte; Research; Resolution; Role; Schistosoma; Schistosomiasis; Scleroderma; Snails; Source; Sterility; System; T-Lymphocyte; Therapeutic; Thrombospondin 1; Transforming Growth Factor beta; Vascular remodeling; adaptive immunity; antigen challenge; biomarker identification; comorbidity; cytokine; egg; experience; hypoxia-induced pulmonary hypertension; interstitial; lung vascular inflammation; monocyte; new therapeutic target; patient subsets; peripheral blood; prevent; protective pathway; pulmonary arterial hypertension; pulmonary vascular disorder; recruit; vascular injury

Project Summary/Abstract Inflammation is central to PH pathogenesis, as a clear trigger of human and experimental disease including autoimmune scleroderma and schistosomiasis infection. Blocking inflammation prevents PH in pre-clinical models, including schistosomiasis and hypoxic sterile inflammation. However, targeting inflammation faces significant challenges, as no therapies have yet been proven to be of clinical benefit. Potential mechanisms that limit this therapeutic approach include: non-targeted immunosuppression suppressing both deleterious and protective pathways; patient-to-patient heterogeneity resulting in only some subsets of patients benefiting, without biomarker identification; and a variable contribution of inflammation to vascular pathology over the disease course. Our research group, working within the context of this PPG submission, is uniquely poised to interrogate mechanisms that link innate and adaptive immunity in PH. We focus on the interplay between complement, monocytes and macrophages in innate immunity, and CD4 T cells in adaptive immunity. Our body of work has demonstrated that Type 2 adaptive immunity driven by Schistosoma exposure (the cause of schistosomiasis, a major PAH etiology), triggers an innate immune response with recruitment of Ly6c+ monocytes, resulting in perivascular thrombospondin-1 (TSP-1) expression, leading to latent TGF-β activation that drives the vascular pathology. We now propose to leverage clearly defined antigenic triggers and mechanistic intermediate and endpoints in Schistosoma-PH to interrogate how complement activates adaptive and innate immunity resulting in vascular remodeling. We will study mechanisms underlying disease persistence versus recovery, focusing on potential dual roles of complement and activated TGF-β as initially inciting of PH, and subsequently suppressing Schistosoma-triggered inflammation and PH as the antigenic burden is cleared. Our third Aim is translational, investigating the peripheral blood immune cell phenotype as it relates to complement and TSP-1 in subjects schistosomiasis, idiopathic and scleroderma-associated pulmonary arterial hypertension, supporting the overall rigor and impact of our studies. Hypothesis: As an innate trigger of adaptive immunity, complement activation is necessary for Type 2 inflammation, monocyte recruitment, and activation of TGF-β by TSP-1, initially contributing to PH and later helping in the resolution of Schistosoma-induced inflammation and PH. Specific Aim 1: To determine that complement is necessary for Type 2 inflammation-driven PH. Specific Aim 2: To determine that complement-dependent TSP-1+ monocyte recruitment contributes to both the initial development and subsequent resolution of Schistosoma-triggered inflammation and PH. Specific Aim 3: To determine that peripheral blood complement levels correlate with leukocyte and cytokine signatures in humans with schistosomiasis, scleroderma and idiopathic PAH. Our overall goal is to identify novel therapeutic targets to safely and effectively target underlying disease drivers in PH, to meaningfully impact the disease course.

项目总结/摘要 炎症是PH发病机制的核心，是人类和实验性疾病的明确触发因素，包括 自身免疫性硬皮病和血吸虫病感染。阻断炎症可预防临床前PH 模型，包括血吸虫病和缺氧无菌炎症。然而，针对炎症面临着 这是一个重大挑战，因为尚未有任何疗法被证明具有临床益处。潜在机制 限制这种治疗方法非靶向免疫抑制包括：抑制有害的 和保护途径;患者间异质性导致仅部分患者受益， 没有生物标志物鉴定;以及在整个研究期间炎症对血管病理学的可变贡献。 病程。我们的研究小组，在这个PPG提交的背景下工作，是独一无二的准备， 询问机制，连接先天性和适应性免疫在PH。我们专注于之间的相互作用 补体、先天免疫中的单核细胞和巨噬细胞以及适应性免疫中的CD 4 T细胞。我们 大量工作已经证明，接触血吸虫会驱动2型适应性免疫（血吸虫病的原因 血吸虫病，一种主要的PAH病因学），通过募集Ly 6c+而触发先天性免疫应答 单核细胞，导致血管周围血小板反应蛋白-1（TSP-1）表达，导致潜在的TGF-β活化 导致了血管病变我们现在建议利用明确定义的抗原触发因子， 血吸虫PH的机制中间体和终点，以询问补体如何激活适应性 和先天免疫导致血管重塑我们将研究疾病的潜在机制 持续与恢复，重点是补体和活化的TGF-β的潜在双重作用， 激发PH，随后抑制血吸虫引发的炎症和PH作为抗原 负担被清除。我们的第三个目标是翻译，研究外周血免疫细胞表型，因为它 与血吸虫病、特发性和硬皮病相关受试者中的补体和TSP-1相关 肺动脉高压，支持我们研究的整体严谨性和影响。假设：作为 获得性免疫的先天触发，补体激活是2型炎症、单核细胞所必需的 TSP-1对TGF-β的募集和激活，最初导致PH，后来帮助解决PH。 血吸虫引起的炎症和PH。具体目标1：确定补体是必要的， 2型炎症驱动的PH。具体目的2：确定补体依赖性TSP-1+单核细胞 招募有助于血吸虫触发的早期发展和随后的解决 具体目标3：确定与炎症和PH相关外周血补体水平 血吸虫病、硬皮病和特发性PAH患者的白细胞和细胞因子特征。我们 总体目标是确定新的治疗靶点，以安全有效地靶向潜在的疾病驱动因素， PH，对疾病进程产生有意义的影响。