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.

项目摘要/摘要 炎症是pH发病机理的核心，是人类和实验性疾病的明显触发因素 自身免疫性硬皮病和血吸虫病感染。阻断感染可防止临床前的pH 模型，包括血吸虫病和缺氧无菌注射。但是，针对注射面 由于尚未证明尚无疗法具有临床利益，因此面临重大挑战。潜在机制 这种限制了这种治疗方法包括：抑制两者都被删除的非靶向免疫抑制 和受保护的途径；患者到患者的异质性仅导致一些受益的患者子集， 没有生物标志物识别；以及炎症对血管病理学的可变贡献 疾病课程。我们的研究小组在此PPG提交的背景下工作，被中毒 询问pH中先天和适应性免疫的机制。我们专注于之间的相互作用 自适应免疫史中的先天免疫史和CD4 T细胞中的补体，单核细胞和巨噬细胞。我们的 工作主体已经证明了由血吸素暴露驱动的2型自适应免疫学（原因 血吸虫病，一种主要的PAH病因），触发了与Ly6c+招募的先天免疫反应 单核细胞，导致周围血小板蛋白-1（TSP-1）表达，导致潜在的TGF-β激活 这驱动了血管病理。现在，我们建议利用明确定义的抗原触发器和 Scistosoma-PH中的机械中间和终点，以询问如何完整激活适应性 和先天的免疫力导致血管重塑。我们将研究疾病潜在的机制 持久性与恢复，重点是完成的潜在双重作用和激活的TGF-β作为最初 煽动pH，随后抑制血吸虫触发的注射和pH作为抗原 负担被消除。我们的第三个目标是翻译，研究了外周血免疫细胞表型 与受试者血吸虫病，特发性和硬皮病相关的受试者的完成和TSP-1有关 肺动脉高压，支持我们研究的总体严格和影响。假设：作为一个 自适应免疫学的先天触发因素，完成激活是2型炎症，单核细胞的必要 TSP-1募集和TGF-β激活，最初有助于pH，然后有助于解决 血吸虫诱导的注射和pH。特定目标1：确定完成是必要的 2型炎症驱动的pH。特定目的2：确定依赖补体的TSP-1+单核细胞 招聘有助于初步发展和随后的分辨率触发的分辨率 炎症和pH。特定目的3：确定外周血补体水平与 人类与血吸虫病，硬皮病和特发性PAH的白细胞和细胞因子特征。我们的 总体目标是确定新颖的治疗靶标，以安全有效地针对潜在的疾病驱动因素 pH，有意义地影响疾病病程。